5, 6-bisaryl-2-pyridine-carboxamide derivatives, preparation and application thereof in therapeutics as urotensin ii receptor antagonists

ABSTRACT

The present invention relates to derivatives of 5,6-bisaryl-2-pyridine-carboxamide, their preparation and their application in therapeutics as antagonists of urotensin II receptors.

This application is a divisional of U.S. patent application Ser. No.12/369,200 filed Feb. 11, 2009, which is a continuation of InternationalPatent Application No. PCT/FR2007/001357, filed Aug. 9, 2007, whichclaims priority to French Patent Application FR 0607283, filed Aug. 11,2006, the contents of all of which are incorporated herein by reference.

The present invention relates to derivatives of5,6-bisaryl-2-pyridine-carboxamide, their preparation and theirapplication in therapeutics as antagonists of urotensin II receptors.

Urotensin II is a cyclic peptide comprising 11 amino acids and isconsidered to be one of the most powerful vasoconstrictors known to date(Ames et al., 1999, Nature 401, 282-286). Its biological activity ismediated by the activation of a receptor with 7 transmembrane domainscoupled to proteins G, called GPR14, renamed UT (Urotensin II Receptor)by the International Union of Basic and Clinical Pharmacology (IUPHAR).Activation of urotensin II receptor leads to mobilization ofintracellular calcium. Urotensin II and its receptor are stronglyexpressed in the cardiovascular system, as well as at the renal andcerebral level and in the endocrine system (Richards and Charles, 2004,Peptides 25, 1795-1802). On isolated vessels, human urotensin II causesvasoconstriction, the intensity of which varies in relation to theparticular region and species (Douglas et al., 2000, Br. J. Phamacol.131, 1262-1274). The administration of urotensin II in an anaesthetizedprimate induces an increase in peripheral vascular resistances and adeterioration of contractility and of cardiac output, which at highdoses may lead to cardiovascular collapse and ultimately to the death ofthe animal (Ames et al., 1999, Nature 401, 282-286). Moreover, urotensinII stimulates the proliferation of the vascular smooth muscle cells andacts in synergy with the mitogenic activity of serotonin and of oxidizedLDLs (Low Density Lipoproteins) (Watanabe et al., 2001, Circulation 104;16-18). On cardiomyocytes in culture, urotensin II induces cellularhypertrophy and an increase in the synthesis of extracellular matrix(Tzanidis A. et al., 2003, Circ. Res. 93, 246-253).

The plasma and urinary levels of urotensin II have been reported to beincreased in a certain number of cardiovascular, renal and metabolicpathologies in humans. These pathologies include arterial hypertension,heart failure, renal failure, diabetes and hepatic cirrhosis (Richardsand Charles, 2004, Peptides 25, 1795-1802; Doggrell, 2004, Expert OpinInvestig Drugs 13, 479-487).

Central effects of urotensin II have also been described (Matsumoto Y.et al., Neurosci. Lett., 2004, 358, 99).

Finally, it has been shown that some tumour cell lines overexpress theurotensin II receptor (Takahashi K. et al., Peptides, 2003, 24, 301).

Antagonists of the urotensin II receptors may be useful for thetreatment of congestive heart failure, ischaemic heart disease,myocardial infarction, cardiac hypertrophy and fibrosis, coronarydiseases and atherosclerosis, systemic and pulmonary arterialhypertension, post-angioplasty restenosis, acute and chronic renalfailure of diabetic and/or hypertensive origin, diabetes, vascularinflammation, and aneurysms. Furthermore, antagonists of the urotensinII receptors may be useful for the treatment of disorders of the centralnervous system, including neurodegenerative diseases, cerebrovascularaccidents, stress, anxiety, aggressiveness, depression andschizophrenia, as well as vomiting and sleep disorders.

Finally, antagonists of the urotensin II receptors may also be usefulfor the treatment of some cancers.

The compounds according to the present invention correspond to formula(I):

in which:

X and Y represent, independently of one another, a nitrogen atom or a—CR3- group, where R3 represents a hydrogen or halogen atom or an alkylor alkoxy group;

U represents a hydrogen atom or a group NHR7, where R7 is a hydrogenatom or an alkyl group;

A represents an aryl, heteroaryl or heterocycloalkyl group;

W represents a halogen atom, an alkyl group or a haloalkyl group;

Z represents a bond, a cycloalkylene group or an alkylene groupoptionally substituted with one or more groups selected from a halogenatom and the alkyl, hydroxy and alkoxy groups;

B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently        of one another, an alkyl, cycloalkyl, hydroxyalkyl or        fluoroalkyl group, or alternatively R4 and R5 form, with the        nitrogen atom to which they are attached, a 5- or 6-membered        ring, such as a pyrrolidinyl or piperidinyl ring, optionally        substituted with an alkyl group,    -   or a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group;

R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an        alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these        groups being optionally substituted with one or more groups        selected from halogen atoms and the alkyl, fluoroalkyl, alkoxy,        hydroxy and —O—CO-alkyl groups, at least one of R1 or R2 being        different from a hydrogen atom,    -   or R1 and R2 together form, with the carbon atom to which they        are attached, a mono- or polycyclic system selected from:        cycloalkyl, indanyl, tetrahydropyranyl, piperidine,        tetrahydronaphthyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl        and adamantyl, said mono- or polycyclic system being optionally        substituted, in any position (including on a nitrogen atom, if        applicable) with one or more groups selected from a halogen atom        and the alkyl, fluoroalkyl, hydroxy, alkoxy, —O—CO-alkyl and        acyl groups;

p represents an integer equal to 0 or 1.

The compounds of formula (I) can have one or more asymmetric carbonatoms.

They can therefore be in the form of enantiomers or of diastereoisomers.These enantiomers, diastereoisomers, and mixtures thereof, includingracemic mixtures, form part of the invention.

The compounds of formula (I) can be in the state of bases or can besalified by acids or bases, notably pharmaceutically acceptable acids orbases. Said salts of addition form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids that can be used, for example, forthe purification or isolation of the compounds of formula (I), also formpart of the invention.

The compounds of formula (I) can also be in the form of hydrates or ofsolvates, namely in the form of associations or combinations with one ormore molecules of water or with a solvent. Said hydrates and solvatesalso form part of the invention.

Among the compounds of formula (I), we may mention the compounds offormula (I′):

in which:

X and Y represent, independently of one another, a nitrogen atom or a—CR3- group, where R3 represents a hydrogen or halogen atom or an alkylor alkoxy group;

A represents an aryl, heteroaryl or heterocycloalkyl group selected fromthe phenyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, pyrazolyl and pyrrolidinone groups, said aryl, heteroaryl orheterocycloalkyl group being optionally substituted in any positionswith 1 to 3 groups selected from a halogen atom and the alkyl,fluoroalkyl, hydroxy, alkoxy, —NRR′, —NR—CO-alkyl, —SO— and —SO₂-alkylgroups, where R and R′ represent, independently of one another, ahydrogen atom or an alkyl group;

W represents a halogen atom, an alkyl group or a fluoroalkyl group;

Z represents a bond, a cycloalkylene group or an alkylene groupoptionally substituted with 1 or 2 groups selected from a halogen atomand the alkyl, hydroxy and alkoxy groups;

B represents:

either a group —NR4R5, where R4 and R5 represent, independently of oneanother, an alkyl, cycloalkyl or fluoroalkyl group, or alternatively R4and R5 form, with the nitrogen atom to which they are attached, a 5- or6-membered ring, such as a pyrrolidinyl or piperidinyl ring, optionallysubstituted with an alkyl group,

or a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl group;

R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an        alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these        groups being optionally substituted with one or more groups        selected from halogen atoms and the alkyl, fluoroalkyl, alkoxy,        hydroxy and —O—CO-alkyl groups, at least one of R1 or R2 being        different from a hydrogen atom,    -   or R1 and R2 together form, with the carbon atom to which they        are attached, a mono- or polycyclic system selected from:        cycloalkyl, indanyl, tetrahydropyranyl, piperidine,        tetrahydronaphthyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl        and adamantyl, said mono- or polycyclic system being optionally        substituted, in any position with one or more groups selected        from a halogen atom and the alkyl, fluoroalkyl, hydroxy, alkoxy,        formyl and acetyl groups;

p represents 0 or 1.

Among the compounds of formula (I) according to the invention, we maymention a subgroup of compounds which is defined as follows:

X and Y represent, independently of one another, a nitrogen atom or a—CR3- group, where R3 represents a hydrogen atom or an alkoxy group;

and/or

U represents a hydrogen atom or a group NHR7, where R7 is a hydrogenatom or an alkyl group;

and/or

A represents an aryl, heteroaryl or heterocycloalkyl group selected fromthe phenyl, benzodioxolyl, thienyl, thiazolyl, pyridinyl, pyrazolyl andpyrrolidinone groups, said aryl or heteroaryl group being optionallysubstituted in any positions with one or more groups selected from ahalogen atom and the cyano, alkyl, haloalkyl, hydroxy, alkoxy,—O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl and —SO₂-alkylgroups, where R and R′ represent, independently of one another, ahydrogen atom or an alkyl group and p is an integer between 1 and 5 andmore particularly between 1 and 3;

and/or

W represents a halogen atom, an alkyl group or a haloalkyl group;

and/or

Z represents a bond or an alkylene group optionally substituted with atleast one group selected from a halogen atom and the alkyl and hydroxygroups;

and/or

B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently        of one another, an alkyl, hydroxyalkyl group, or alternatively        R4 and R5 form, with the nitrogen atom to which they are        attached, a 5- or 6-membered ring, such as a pyrrolidinyl or        piperidinyl ring,    -   or a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group;

and/or

R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an        alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these        groups being optionally substituted with one or more hydroxy        groups, at least one of R1 or R2 being different from a hydrogen        atom,    -   or R1 and R2 together form, with the carbon atom to which they        are attached, a mono- or polycyclic system selected from:        cycloalkyl, indanyl, tetrahydropyranyl, piperidine,        bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said        mono- or polycyclic system being optionally substituted, in any        position (including on a nitrogen atom, if applicable) with one        or more groups selected from the alkyl, hydroxy, acetyl and        alkoxy groups;

and/or

p represents an integer equal to 0 or 1.

Among the compounds of formula (I) according to the invention, we maymention a second subgroup of compounds for which X and Y represent,independently of one another, a nitrogen atom or a —CR3- group, where R3represents a hydrogen or halogen atom or an alkyl or alkoxy group.

More particularly, among the compounds of formula (I) of the secondsubgroup according to the invention, we may mention a subgroup ofcompounds for which X and Y represent, independently of one another, anitrogen atom or a —CR3- group, where R3 represents a hydrogen atom oran alkoxy group.

Among the compounds of formula (I) according to the invention, we maymention a third subgroup of compounds for which U represents a hydrogenatom or a group NHR7, where R7 is a hydrogen atom or an alkyl group.

Among the compounds of formula (I) according to the invention, we maymention a fourth subgroup of compounds for which A represents an aryl,heteroaryl or heterocycloalkyl group optionally substituted.

More particularly, among the compounds of formula (I) of the fourthsubgroup according to the invention, we may mention a subgroup ofcompounds for which A represents an aryl, heteroaryl or heterocycloalkylgroup selected from the phenyl, benzodioxolyl, thienyl, thiazolyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl andpyrrolidinone groups, said aryl, heteroaryl or heterocycloalkyl groupbeing optionally substituted in any positions with one or more groupsselected from a halogen atom and the cyano, alkyl, haloalkyl, hydroxy,alkoxy, —O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl, —SO— and—SO₂-alkyl groups, where R and R′ represent, independently of oneanother, a hydrogen atom or an alkyl group and p is an integer between 1and 5.

Even more particularly, among the compounds of formula (I) of the fourthsubgroup according to the invention, we may mention a subgroup ofcompounds for which A represents a group selected from the phenyl,benzodioxolyl, thienyl, thiazolyl, pyridinyl, pyrazolyl andpyrrolidinone groups, said aryl or heteroaryl group being optionallysubstituted in any positions with one to three groups selected from ahalogen atom and the cyano, alkyl, haloalkyl, hydroxy, alkoxy,—O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl and —SO₂-alkylgroups, where R and R′ represent, independently of one another, ahydrogen atom or an alkyl group and p is an integer between 1 and 3.

Among the compounds of formula (I) according to the invention, we maymention a fifth subgroup of compounds for which W represents a halogenatom, an alkyl group or a haloalkyl group.

Among the compounds of formula (I) according to the invention, we maymention a sixth subgroup of compounds for which Z represents a bond, acycloalkylene group or an alkylene group optionally substituted with 1or 2 groups selected from a halogen atom and the alkyl, hydroxy andalkoxy groups.

More particularly, among the compounds of formula (I) of the sixthsubgroup according to the invention, we may mention a subgroup ofcompounds for which Z represents a bond or an alkylene group optionallysubstituted with at least one group selected from a halogen atom and thealkyl and hydroxy groups.

Among the compounds of formula (I) according to the invention, we maymention a seventh subgroup of compounds for which B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently        of one another, an alkyl, cycloalkyl, hydroxyalkyl or        fluoroalkyl group, or alternatively R4 and R5 form, with the        nitrogen atom to which they are attached, a 5- or 6-membered        ring, such as a pyrrolidinyl or piperidinyl ring, optionally        substituted with an alkyl group,    -   or a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group.

More particularly, among the compounds of formula (I) of the seventhsubgroup according to the invention, we may mention a subgroup ofcompounds for which B represents a group —NR4R5, where R4 and R5represent, independently of one another, an alkyl, cycloalkyl,hydroxyalkyl or fluoroalkyl group, or alternatively R4 and R5 form, withthe nitrogen atom to which they are attached, a 5- or 6-membered ring,such as a pyrrolidinyl or piperidinyl ring, optionally substituted withan alkyl group.

Even more particularly, among the compounds of formula (I) of theseventh subgroup according to the invention, we may mention a subgroupof compounds for which B represents a group —NR4R5, where R4 and R5represent, independently of one another, an alkyl, hydroxyalkyl orfluoroalkyl group, or alternatively R4 and R5 form, with the nitrogenatom to which they are attached, a 5- or 6-membered ring, such as apyrrolidinyl or piperidinyl ring.

More particularly, among the compounds of formula (I) of the seventhsubgroup according to the invention, we may mention a subgroup ofcompounds for which B represents a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group.

Among the compounds of formula (I) according to the invention, we maymention an eighth subgroup of compounds for which R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an        alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these        groups being optionally substituted with one or more groups        selected from halogen atoms and the alkyl, fluoroalkyl, alkoxy,        hydroxy and —O—CO-alkyl groups, at least one of R1 or R2 being        different from a hydrogen atom,    -   or R1 and R2 together form, with the carbon atom to which they        are attached, a mono- or polycyclic system selected from:        cycloalkyl, indanyl, tetrahydropyranyl, piperidine,        tetrahydronaphthyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl        and adamantyl, said mono- or polycyclic system being optionally        substituted, in any position (including on a nitrogen atom, if        applicable) with one or more groups selected from a halogen atom        and the alkyl, fluoroalkyl, hydroxy, alkoxy, —O—CO-alkyl and        acyl groups.

More particularly, among the compounds of formula (I) of the eighthsubgroup according to the invention, we may mention a subgroup ofcompounds for which R1 and R2 represent, independently of one another, ahydrogen atom or an alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolylgroup, these groups being optionally substituted with one or more groupsselected from halogen atoms and the alkyl, fluoroalkyl, alkoxy, hydroxyand —O—CO-alkyl groups, at least one of R1 or R2 being different from ahydrogen atom.

Even more particularly, among the compounds of formula (I) of the eighthsubgroup according to the invention, we may mention a subgroup ofcompounds for which R1 and R2 represent, independently of one another, ahydrogen atom or an alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolylgroup, these groups being optionally substituted with one or morehydroxy groups, at least one of R1 or R2 being different from a hydrogenatom.

More particularly, among the compounds of formula (I) of the eighthsubgroup according to the invention, we may mention a subgroup ofcompounds for which R1 and R2 together form, with the carbon atom towhich they are attached, a mono- or polycyclic system selected from:cycloalkyl, indanyl, tetrahydropyranyl, piperidine, tetrahydronaphthyl,bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- orpolycyclic system being optionally substituted, in any position(including on a nitrogen atom, if applicable) with one or more groupsselected from a halogen atom and the alkyl, hydroxy and alkoxy groups.

Even more particularly, among the compounds of formula (I) of the eighthsubgroup according to the invention, we may mention a subgroup ofcompounds for which R1 and R2 together form, with the carbon atom towhich they are attached, a mono- or polycyclic system selected from:cycloalkyl, indanyl, tetrahydropyranyl, piperidine,bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- orpolycyclic system being optionally substituted, in any position(including on a nitrogen atom, if applicable) with one or more groupsselected from the alkyl, hydroxy and alkoxy groups.

Even more particularly, among the compounds of formula (I) of the eighthsubgroup according to the invention, we may mention a subgroup ofcompounds for which R1 and R2 together form, with the carbon atom towhich they are attached, a mono- or polycyclic system selected from:cycloalkyl, indanyl, tetrahydropyranyl, piperidine,bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- orpolycyclic system being optionally substituted, on a carbon atom, withone or more groups selected from the alkyl, hydroxy and alkoxy groups.

Even more particularly, among the compounds of formula (I) of the eighthsubgroup according to the invention, we may mention a subgroup ofcompounds for which R1 and R2 together form, with the carbon atom towhich they are attached, a mono- or polycyclic system selected from:cycloalkyl, indanyl, tetrahydropyranyl, piperidine,bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- orpolycyclic system being optionally substituted, on a nitrogen atom, witha group selected from the alkyl and acyl groups.

Among the compounds of formula (I) according to the invention, we maymention a ninth subgroup of compounds for which p represents an integerequal to 0 or 1.

Within the scope of the present invention, and unless stated otherwisein the text, the following definitions are used:

-   -   halogen atom: a fluorine, chlorine, bromine or iodine atom;    -   alkyl group: a saturated linear aliphatic group, comprising 1 to        5 carbon atoms or when the alkyl chain has at least three carbon        atoms it can be linear, branched or partially cyclized. As        examples, we may mention the methyl, ethyl, propyl, isopropyl,        butyl, isobutyl, tertbutyl, pentyl, methylene-cyclopropyl        groups;    -   alkylene group: an alkyl group as defined above, which is        divalent. As examples, we may mention a dimethylene (—CH₂—CH₂—),        propylene, butylene, ethylene, or 2-methylpropylene group;    -   cycloalkyl group: a saturated cyclic group, which has from 3 to        8 carbon atoms and which is cyclic. As examples, we may mention        the cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl groups;    -   heterocycloalkyl group: a cycloalkyl group as defined above, in        which one or two carbons have been substituted with a nitrogen        atom. As examples, we may mention the pyrrolidinone group and        the piperidine group;    -   aryl group: a monocyclic aromatic group comprising 5 or 6 carbon        atoms, for example a phenyl group;    -   heteroaryl group: a cyclic aromatic group comprising 5 or 6        atoms, one or more of which are heteroatoms such as N and/or S.        As examples of heteroaryl groups, we may mention a thienyl,        thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,        pyrazolyl group;    -   cycloalkylene group: a cycloalkyl group as defined above which        is divalent;    -   fluoroalkyl group: an alkyl group as defined above, in which one        or more hydrogen atoms have been substituted with a fluorine        atom. As an example, we may mention the trifluoromethyl group;    -   alkoxy group: a group of formula —O-alkyl where the alkyl group        is as defined previously.

Among the compounds described in the present invention, we may mention asubgroup of compounds corresponding to formula (I) in which:

X and Y represent, independently of one another, a nitrogen atom or a CHgroup;

A represents a phenyl, pyridinyl, or pyrrolidinone group, substituted inany positions with 1 to 2 groups selected from a halogen atom, such aschlorine or fluorine, and the alkyl, trifluoromethyl, methoxy andN,N-dimethylamine groups;

U represents a hydrogen atom or a group NHR7, where R7 is a hydrogenatom;

W represents a chlorine atom or a trifluoromethyl group;

Z represents a bond or an alkylene group optionally substituted with amethyl group;

B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently        of one another, an alkyl group or alternatively R4 and R5 form,        with the nitrogen atom to which they are attached, a 5- or        6-membered ring,    -   or heterocycles of the following formula:

where m=1 or 2 and R6 represents an ethyl or methyl group;

R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an        isopropyl, tertbutyl group;    -   or R1 and R2 together form, with the carbon atom to which they        are attached, a mono- or polycyclic system selected from:        cycloalkyl (such as cyclopentyl, cyclohexyl, or cycloheptyl),        tetrahydropyranyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and        adamantyl, said cycloalkyl group being optionally substituted in        positions 3 and 4 with a methyl, hydroxy or methoxy group or one        or two halogen atoms such as fluorine;

p represents 0 or 1.

We may also mention a second subgroup of compounds among the preferredcompounds corresponding to formula (I) in which:

X represents a nitrogen atom and Y represents a CH group;

A represents a phenyl or pyridinyl group, substituted in positions 2, 4,5 and 6 by one or two groups selected from a halogen atom, such aschlorine or fluorine, and the alkyl groups, such as methyl, ethyl orisopropyl, trifluoromethyl, methoxy and N,N-dimethylamine;

U represents a hydrogen atom or a group NHR7, where R7 is a hydrogenatom;

W represents a chlorine atom or a trifluoromethyl group;

Z represents a bond or an ethylene, propylene or methylpropylene group;

B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently        of one another, a methyl, ethyl or propyl group or form together        with the nitrogen atom to which they are attached a 5- or        6-membered ring,    -   or a heterocycle of the following formula:

R1 and R2 represent:

-   -   either R1 is a hydrogen atom and R2 an isopropyl, tertbutyl        group, the carbon atom bearing groups R1 and R2 adopting the        absolute configuration S,    -   or R1 and R2 together form, with the carbon atom to which they        are attached, a cycloalkyl group (such as cyclohexyl or        cycloheptyl), and adamantyl, said cycloalkyl group being        optionally substituted in positions 3 and 4 with a methyl,        hydroxy or methoxy group,

p represents 0 or 1.

Among the compounds according to the invention, we may notably mentionthe following compounds:

-   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-4-methoxy-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-difluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-ethoxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dichlorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-fluoro-6-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methyl-5-(1-methylethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-chloro-5-(2-methoxyethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyrazin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(methoxymethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-chloro-5-(1-methylethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-{[(5-[2-chloro-5-(dimethylamino)phenyl]-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethyl-6-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methyl-5-propylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)-4-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-ethoxy-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)-2-fluoropropoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)-5-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(2-methoxyethoxy)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(methoxymethyl)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methyl-5-(1-methylethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methyl-5-(2-methylpropoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(cyclopropylmethoxy)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methyl-5-propoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-2,3-dihydro-1H-indene-2-carboxylic    acid-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclopentanecarboxylic    acid-   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[2.2.1]heptane-2-carboxylic    acid hydrochloride-   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}phenylalanine-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic    acid-   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-4-phenylbutanoic    acid-   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-4-(1H-indol-3-yl)butanoic    acid-   ({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)(phenyl)acetic    acid-   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-3-cyclohexylpropanoic    acid-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid-   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}-alpha-methylphenylalanine-   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}-3-methylisovaline-   2-({[6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[(1-ethylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-phenylpyridin-2-yl)carbonyl]amino}adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   9-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-{[(2-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3.4′-bipyridin-6-yl)carbonyl]amino}adamantane-2-carboxylic    acid hydrochloride-   2-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylic    acid hydrochloride-   3-[({4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoic    acid-   3-({[5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoic    acid hydrochloride-   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}-3-hydroxyphenylalanine    hydrochloride-   2-({[6-{4-chloro-3-[2-(1-methylpyrrolidin-2-yl)ethoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[2-(1-methylpiperidin-2-yl)ethoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(trifluoromethyl)phenyl]pyridin-2-yl)carbonyl]amino}adamantane-2-carboxylic    acid hydrochloride-   2-({[6-(4-chloro-3-{3-[cyclopropyl(methyl)amino]propoxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(dimethylamino)phenyl]pyridin-2-yl)carbonyl]amino}adamantane-2-carboxylic    acid hydrochloride-   1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   4-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)tetrahydro-2H-pyran-4-carboxylic    acid hydrochloride-   (3R)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic    acid hydrochloride-   2-[({6-[4-chloro-3-(3-piperidin-1-ylpropoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[3-(dimethylamino)butoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-[({6-[4-chloro-3-(2-piperidin-1-ylethoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylic    acid hydrochloride-   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic    acid hydrochloride-   2-[({6-[4-chloro-3-(2-pyrrolidin-1-ylethoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylic    acid hydrochloride-   2-[({6-[4-chloro-3-(3-pyrrolidin-1-ylpropoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylic    acid hydrochloride-   2-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-methyl-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylcyclohexanecarboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[3-(dimethylamino)-1-methylpropoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-methoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   2-({[6-(4-chloro-3-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   2-({[6-(4-chloro-3-{[(2S)-3-(dimethylamino)-2-hydroxypropyl]oxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   acetyl-4-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)piperidine-4-carboxylic    acid hydrochloride-   2-({[6-{4-chloro-3-[2-(diethylamino)ethoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   [1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexyl]acetic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[3-amino-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-hydroxycyclohexanecarboxylic    acid hydrochloride-   cis-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-methoxycyclohexanecarboxylic    acid hydrochloride-   trans-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-methoxycyclohexanecarboxylic    acid hydrochloride-   trans-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(methylsulphonyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(methylsulphonyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-methyl-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(5-[2-(acetylamino)phenyl]-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}-D-valine    hydrochloride-   1-{[(2-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2′-methyl-3.3′-bipyridin-6-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(2-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-4′-methyl-3.3′-bipyridin-6-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-[({6-[4-chloro-3-(2-pyrrolidin-1-ylethoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[4-(dimethylamino)butoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(1-methylethyl)phenyl]pyridin-2-yl)carbonyl]amino}-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-chloro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,5-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4-fluoro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-(4-chloro-3-{3-[methyl(propyl)amino]propoxy}phenyl)-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)-2-methylpropoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-3-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-propylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-fluoro-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic    acid hydrochloride-   1-({[3-chloro-2′-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-2,3′-bipyridin-6′-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,5-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cycloheptanecarboxylic    acid hydrochloride-   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{3-[3-(dimethylamino)propoxy]-4-ethylphenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-cyclobutylpropanoic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylthiophen-3-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-cyclopropylpropanoic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-hydroxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4,5-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-methyl-1,3-thiazol-4-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   4-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)oxepane-4-carboxylic    acid hydrochloride-   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-cyanophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3-fluoro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-6-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-(4-chloro-3-{3-[(2-hydroxyethyl)(methyl)amino]propoxy}phenyl)-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4,5-difluoro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(6-methyl-1,3-benzodioxol-5-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-diethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[5-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-(difluoromethyl)-2,3′-bipyridin-6′-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methylphenyl]-3-[methylamino]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-ethyl-3-methyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-{[(5-[2-chloro-4-(dimethylamino)phenyl]-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-chloro-5-(trifluoromethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride-   1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dichlorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-difluorocyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-(methylamino)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-methoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic    acid hydrochloride-   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic    acid hydrochloride

In accordance with the invention, the compounds of general formula (I)can be prepared according to the method given below, shown in scheme 1.

When, in the starting compound of formula (XI), X represents a nitrogenatom, Y represents a carbon atom (i.e. a group of formula —CR₃— asdefined with reference to the compounds of formula (I) according to theinvention) and U represents a hydrogen atom, or alternatively Xrepresents a carbon atom, Y represents a nitrogen atom and U representsa hydrogen atom, or alternatively X and Y represent a nitrogen atom andU represents a hydrogen atom, then we can carry out, in a stage (i), acoupling reaction of the SUZUKI type, catalysed by a palladium (0)derivative such as tetrakis(triphenylphosphine)palladium (0)[Pd(PPh₃)₄], between the compound of formula (XI) (where Q=OH or Br andT=halogen atom, such as a bromine or iodine atom) and a boronic acid offormula (IX), where GP represents a benzyl group optionally substitutedwith one or more alkoxy groups, in the presence of a base such aspotassium phosphate and in a solvent such as N,N-dimethylformamide (DMF)at a temperature of about 95° C. This reaction permits regioselectivesubstitution of function T with the phenoxy nucleus to give compound(VIII).

The OH function of compound (VIII) is then converted to a leaving groupsuch as trifluoromethanesulphonate (OTf), in stage (ii), by means oftrifluoromethanesulphonic anhydride in the presence of a base such astriethylamine (TEA) and in a solvent such as dichloromethane (DCM) togive the compound of formula (VII).

The trifluoromethanesulphonate group thus obtained makes it possible,owing to its reactivity, to introduce, in stage (iii), the nucleus A byan organopalladium coupling reaction of the type:

-   -   either SUZUKI, between compound (VII) and a boronic acid or        ester of respective formulae A-B(OH)₂ or

in the presence of a catalytic amount of a palladium derivative such asPd(PPh₃)₄, in the presence of a base such as potassium phosphate and ofa solvent such as DMF, at a temperature of 90° C.;

-   -   or STILLE, between compound (VII) and an aryltributylstannane or        heteroarylstannane derivative ASnBu₃ in the presence of a        catalytic amount of copper iodide (CuI) and of a derivative of        palladium (II) such as        [1,1′-bis(cyclopentadienyldiphenylphosphino)ferrocene]palladium (II)        dichloride [PdCl₂(dppf)] and of a solvent such as 1,4-dioxan at        a temperature of 90° C.;    -   or HARTWIG-BUCHWALD, between compound (VII) and an amide such as        2-pyrrolidinone, in the presence of a catalytic amount of a        phosphine such as        9,9-dimethyl-4,5-bis-(diphenylphosphino)xanthene (XantPhos) and        of a derivative of palladium (0) such as        tris(dibenzylideneacetone)dipalladium (0) [Pd₂(dba)₃], using a        base such as caesium carbonate, and in a solvent such as DMF at        a temperature of 70° C.

We thus obtain compound (VI).

Alternatively, in the starting compound of formula (XI), when X and Yrepresent carbon atoms and U represents a hydrogen atom, Q an iodineatom and T a bromine atom, or alternatively X and Y represent a nitrogenatom and U represents a group NHR (as defined with reference to thecompounds of formula (I) according to the invention), Q and T atoms ofchlorine, bromine or iodine, the order of introduction of groups A andphenoxy on the starting phenyl nucleus is reversed (scheme 1).

In this case, a first reaction of the SUZUKI type (stage (iv)) with aboronic acid A-B(OH)₂ permits the selective introduction of a group A inplace of the halogen atom Q. The reaction is carried out in the presenceof a catalytic amount of a palladium derivative such as Pd(PPh₃)₄ and ofa base such as caesium carbonate, in a solvent such as DMF at atemperature of 90° C. Then a second reaction of the SUZUKI type iscarried out (stage (v)) between the boronic ester (XII) or the boronicacid (IX) and compound (X), in the presence of a catalytic amount of apalladium derivative such as Pd(PPh₃)₄ and of a base such as caesiumcarbonate, in a solvent such as DMF at a temperature of 90° C. We thusobtain compound (VI).

Deprotection of the phenol function of the compound of formula (VI) byboron tribromide at −78° C., trifluoroacetic acid (TFA) at roomtemperature or hydrogen chloride at 0° C. in DCM (stage (vi)) leads tothe compound of formula (V).

The introduction of group Z—B in stage (vii) can be carried out:

-   -   either by alkylation of compound (V) with a chlorine derivative        Cl—Z—B in the presence of a weak inorganic base such as caesium        carbonate and in a polar aprotic solvent such as DMF at a        temperature between 80 and 100° C., such as 90° C.,    -   or by MITSUNOBU reaction between compound (V) and an alcohol of        formula HO—Z—B in the presence of triphenylphosphine,        diisopropyl azodicarboxylate (DIAD), and a catalytic amount of a        weak organic base such as TEA at 0° C. in an aprotic solvent        such as tetrahydrofuran (THF).

The compound of formula (IV) is then saponified in stage (viii), bymeans of a strong inorganic base such as potassium hydroxide in awater/methanol mixture maintained at room temperature (RT) or heatedunder reflux, to give, after acidification with a strong acid such as 1Nhydrochloric acid (HCl), compound (III).

Within the scope of the present invention, room temperature means atemperature between 20 and 25° C.

A peptide coupling reaction (stage (ix)) between compound (III) andamines of formula (II) in the presence of a coupling agent such ascarbonyldiimidazole (CDI),N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminiumtetrafluoroborate (TBTU) or N-[3-(dimethylamino)propyl-N′-ethylcarbodiimide hydrochloride (EDC.HCl) and of an organic base such asN,N′-diisopropylethylamine (DIEA) and in a polar aprotic solvent such asDMF at room temperature leads to the compounds of formula (I) accordingto the present invention.

Scheme 2 describes the synthesis of the boronic derivatives (IX) and(XII).

The Case when W═CF₃

2-Amino-5-nitrophenol (XVI) is converted to the iodine derivative (XV)by a SANDMEYER reaction in an aqueous environment at 0° C., in thepresence of sodium iodide and with a co-solvent such asdimethylsulphoxide (DMSO). Protection of the phenol function (stage i)by a benzyl group is effected with a halogen derivative such as benzylbromide in the presence of a base such as potassium carbonate (K₂CO₃) ina solvent such as DMF at 60° C. Substitution of the iodine atom with thetrifluoromethyl group (Eur. J. Org. Chem. (2003) pp. 1559-1568), carriedout with trifluoromethyltrimethylsilane in the presence of CuI andpotassium fluoride in a solvent such as N-methylpyrrolidinone (NMP) at45° C. (stage ii), leads to compound (XIV) which, after reduction of thenitro function to an amino function by a reducing agent such as iron at70° C. in an ethanol (EtOH)/water/acetic acid (AcOH) mixture, isconverted to the iodine derivative (XIII) by means of a second SANDMEYERreaction (stage iii).

In stage (iv), a reaction of metal-halogen exchange effected betweencompound (XIII) and isopropyl magnesium chloride (iPrMgCl) at −50° C. ina solvent such as THF, followed by addition of triisopropylborate, leadsafter acidolysis with an acid such as HCl 5N, to boronic acid (IX).

The Case when W═Cl

Protection of the 2-chloro-5-iodophenol (XVIIa) by a benzyl orpara-methoxybenzyl group as described in stage (i) leads to the iodinederivative (XVII) which can be converted:

-   -   either, in stage (iv), to boronic acid (IX) as described        previously,    -   or, in stage (v), to boronic ester (XII) by a coupling reaction        with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-dioxaborolane in the        presence of a base such as potassium acetate (KOAc) and a        catalytic amount of a palladium derivative (II) such as        [PdCl₂(dppf)], in a solvent such as DMSO at 100° C.

Alternatively, a subgroup of compounds of formula (Ia) according to thepresent invention, where group A represents a 2,6-dimethoxybenzenenucleus, was prepared in the following way (scheme 3):

-   -   Condensation of 2,6-dimethoxybenzaldehyde on 2-cyanoacetic acid        (stage i) in the presence of ammonium acetate and a base such as        pyridine, heating under reflux of a solvent such as toluene,        leads to derivative (XX).    -   Derivative (XX) is then treated with diisobutylaluminium hydride        (DIBAL-H) at 0° C. in a solvent such as toluene. The aldehyde        thus obtained is reacted (stage ii) with ethyl 2-azido acetate        at −10° C. in the presence of a base such as sodium ethoxide in        a solvent such as ethanol to obtain the diene (XIX). In stage        (iii), treatment of diene (XIX) with triphenylphosphine at RT in        a solvent such as DCM leads to azatriphenylphosphoranylidene        (XVIII).    -   Reaction (stage iv) between derivative (XVIII) and the        aldehyde (XVII) in a solvent such as acetonitrile leads, via the        cyclization in situ at 100° C. of an intermediate imine        according to an electrocyclic cyclization/dehydrogenation        multistep process, to the pyridine derivative (IVa).    -   The steps of alkylation or MITSUNOBU reaction (stage v),        saponification (stage vi) then peptide coupling (stage vii)        described previously in scheme 1 and applied to derivative (IVa)        lead to the compounds of formula (Ia) according to the present        invention.

In schemes 1 and 2, when the method of preparation of the startingcompounds, the intermediates and the reagents is not described, they areavailable commercially or are described in the literature, oralternatively can be prepared according to methods that are known by aperson skilled in the art.

The following examples illustrate the preparation of some compoundsaccording to the invention. The numbering of the compounds in theexamples refers to the table given later showing the chemical structuresand physical properties of some compounds according to the invention.

The following abbreviations are used:

-   EtOAc Ethyl acetate-   AcOH Acetic acid-   BSA N,O-Bis(trimethylsilyl)acetamide-   CDI Carbonyldiimidazole-   CuI Copper iodide-   DCM Dichloromethane-   DIBAL-H Diisobutylaluminium hydride-   DIAD Diisopropyl azodicarboxylate-   DME Dimethoxyethane-   DMF Dimethylformamide-   DMSO Dimethyl sulphoxide-   EDC.HCl N-[3-(Dimethylamino)propyl-N′-ethyl carbodiimide    hydrochloride-   EtOH Ethanol-   h Hour(s)-   HCl Hydrochloric acid-   K₂CO₃ Potassium carbonate-   KOAc Potassium acetate-   K₃PO₄ Potassium phosphate or tripotassium tetraoxophosphate-   Na₂CO₃ Sodium carbonate-   NH₄Cl Ammonium chloride-   NaHCO₃ Sodium bicarbonate-   Na₂SO₄ Sodium sulphate-   NMP N-methylpyrrolidinone-   PdCl₂ (dppf) [1    μl′-bis(Cyclopentadienyldiphenylphosphino)ferrocene]palladium (II)    dichloride-   Pd(PPh₃)₄ Tetrakis (triphenylphosphine) palladium (0)-   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium (0)-   TBTU    N-[(1H-Benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium    tetrafluoroborate-   TEA Triethylamine-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   RT Room temperature

EXAMPLE 11-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid Compound No. 12 1.1. (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile

Add, one after another, 1.13 g (14.7 mmol) of ammonium acetate, 40.4 mL(500 mmol) of pyridine and 31.2 g (367 mmol) of 2-cyanoacetic acid to asolution of 61 g (367 mmol) of 2,6-dimethoxybenzaldehyde in 360 mL oftoluene. Reflux the reaction mixture for 15 h, distilling thetoluene-water azeotrope in Dean-Stark apparatus. Take up the solution in500 mL toluene and 40 mL pyridine and reflux again for 48 h in theDean-Stark apparatus. After concentration under reduced pressure, takeup the residue in 800 mL of dichloromethane (DCM) and wash successivelywith 1 L of 1N HCl aqueous solution, 500 mL of saturated aqueoussolution of sodium carbonate (Na₂CO₃) and 1 L of water. After dryingover sodium sulphate (Na₂SO₄) and concentration under reduced pressure,we obtain 62 g of (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in the formof brown oil, which is used “as is” in the next stage.

Yield=89%

1.2. (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde

Add 355 mL of a 1M solution of diisobutylaluminium hydride (DIBAL-H)(355 mmol) in toluene to a solution of 61 g (322 mmol) of(2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in 600 mL of anhydrous tolueneunder argon and cooled to 0° C., maintaining the temperature at 0° C.Then bring the reaction mixture to room temperature (RT) and stir for 3h. Then add 13 mL (322 mmol) of methanol and then, dropwise, 170 g (174mmol) of an aqueous solution of sulphuric acid at 10 wt. %. Stir thesuspension for one hour, then filter on a celite bed. Wash the filtratewith 500 mL of water then dry over Na₂SO₄ and concentrate under reducedpressure. Take up the residue obtained in 500 mL of DCM and filter in asilica column, eluting with DCM. After concentration under reducedpressure, we obtain 37 g of (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde inthe form of colourless oil.

Yield=60%.

1.3. Ethyl (2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate

Add dropwise, while stirring, a solution of 37 g (192 mmol) of(2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde and 85.7 g (664 mmol) of ethyl2-azidoacetate in 200 mL of absolute ethanol EtOH to a solution of 15.5g (673 mmol) of sodium in 500 mL of absolute EtOH cooled to −10° C. andkept under argon, maintaining the temperature at −10° C. After stirringat −10° C. for 3 h, stir the reaction mixture for 15 h at RT, then pourinto 600 mL of an aqueous solution of ammonium chloride (NH₄Cl) at 30wt. %. After filtration on a frit and rinsing with 2×200 mL of water,take up the precipitate in 600 mL of DCM, dry over Na₂SO₄ andconcentrate under reduced pressure, which leads to 42 g of ethyl(2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate in the form ofa yellow solid.

Yield=80%

M.p. (° C.)=138.

1.4 Ethyl(2E,4E)-5-(2,6-dimethoxyphenyl)-2-[triphenylphosphoranylidene)amino]penta-2,4-dienoate

Add, dropwise, a solution of 5 g of ethyl(2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate (16.5 mmol) in60 mL of DCM to a solution of 4.37 g (16.7 mmol) of triphenylphosphinein 40 mL of DCM. Stir the reaction mixture for 2 h at RT, thenconcentrate under reduced pressure. Solidify the residue obtained in 100mL of isopropyl ether, then filter on a frit and rinse with 50 mL ofisopropyl ether, giving 7.9 g of ethyl(2E,4E)-5-(2,6-dimethoxyphenyl)-2-[(triphenylphosphoranylidene)amino]penta-2,4-dienoatein the form of a white solid.

Yield=91%

M.p. (° C.)=172

1.5. Ethyl6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate

Reflux a solution of 7.54 g (14 mmol) of ethyl(2E,4E)-5-(2,6-dimethoxyphenyl)-2-[(triphenylphosphoranylidene)amino]penta-2,4-dienoateand 2.42 g (15.4 mmol) of 4-chloro-3-hydroxybenzaldehyde in 280 mL ofanhydrous acetonitrile for 96 h. After cooling to RT, concentrate thereaction mixture under reduced pressure and purify the residue obtainedby silica gel column chromatography, eluting with a cyclohexane/ethylacetate (EtOAc) gradient from 0 to 30% of EtOAc. After concentrationunder reduced pressure, we obtain 2.4 g of ethyl6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylatein the form of white powder.

Yield=41%

M.p. (° C.)=182

1.6. Ethyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxy-phenyl)pyridine-2-carboxylate

Add 0.257 g (2.11 mmol) of 3-chloro-N,N-dimethylpropane-1-aminehydrochloride and 3.40 g (1.34 mmol) of caesium carbonate to a solutionof 0.5 g (1.21 mmol) of ethyl6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylatein 20 mL of anhydrous DMF under argon. Stir the reaction mixture for 15min at RT then heat for 2 h at 80° C. After cooling to RT, add 1 mL ofan aqueous solution of citric acid at 5% and concentrate the whole underreduced pressure. Take up the residue in 50 mL of EtOAc and wash with 10mL of a 5% solution of Na₂CO₃ and then 10 mL of water. After drying overNa₂SO₄ and concentration under reduced pressure, purify the residue bysilica gel column chromatography, eluting with a DCM/methanol gradientfrom 1 to 15% of methanol. After concentration under reduced pressure,we obtain 0.55 g of ethyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylatein the form of oil.

Yield=91%

1.7.6-{4-Chloro-3-[3-(dimethylamino)propoxy-]phenyl}-5-(2,6-dimethoxy-phenyl)pyridine-2-carboxylicacid

Add 3.16 g (56.38 mmol) of potassium hydroxide to a solution of 5.63 g(11.28 mmol) of ethyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylatein 132 mL of EtOH. Reflux the reaction mixture for 2 h and thenconcentrate under reduced pressure. Take up the residue obtained in 10mL of water, then neutralize with 56.5 mL (56.5 mmol) of a 1N HClaqueous solution. The precipitate obtained is filtered on a frit andrinsed with 2×10 mL of water. After drying under reduced pressure, weobtain 5.25 g of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylicacid in the form of white powder.

Yield=100%

M.p. (° C.)=215

1.8.1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid

Add, under argon, 0.74 mL (0.41 mmol) of diisopropylethylamine and 409mg (1.28 mmol) of TBTU to a solution of 200 mg (0.42 mmol) of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylicacid in 50 mL of anhydrous DMF. In parallel, heat, while stirring underargon, a mixture of 84 mg (0.59 mmol) of 2-aminocyclohexane-2-carboxylicacid and 0.18 mL (0.76 mmol) of N,O-bis(trimethylsilyl)acetamide (BSA)in 5 mL of anhydrous acetonitrile to 90° C. After 2 h, the mixture hasdissolved completely. Cool the solution to RT, then add it to thesolution of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2carboxylic acid activated with TBTU. After stirring for 18 h at RT, add10 mL of 0.5N HCl aqueous solution and continue stirring for 3 h. Thendistribute the reaction mixture in a mixture of 20 mL of EtOAc/ether 1:1and 10 mL of water. After extraction, extract the aqueous phase againwith 10 mL of 1:1 ether/EtOAc mixture. Combine the organic phases, washwith 2×10 mL of water, dry over Na₂SO₄ and concentrate under reducedpressure. Then purify the residue by reverse-phase HPLC(RP18) elutingwith a 0.01N HCl/acetonitrile gradient from 5% to 100% of acetonitrile.After concentration under reduced pressure and lyophilization, we obtain106 mg of1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride in the form of white powder.

Yield=41%

M.p. (° C.)>200.

M=C₃₂H₃₈ClN₃O₆=595; M+H=596

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.70 (s, 1H); 7.80 (d, 1H); 7.65 (d, 1H)7.15 (m, 2H); 7.05 (d, 1H); 6.60 (d, 1H); 6.50 (d, 2H); 3.85 (t, 2H);3.35 (s, 6H); 2.75 (m, 2H); 2.45 (s, 6H); 2.15 (m, 2H); 1.90 (m, 2H)1.55 (m, 4H); 1.25 (m, 4H).

EXAMPLE 29-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylicacid hydrochloride Compound No. 25 2.1.9-aminobicyclo[3.3.1.]nonane-9-carbonitrile

Add successively 21 mL of water, 1.12 g (22.8 mmol) of sodium cyanide,4.52 mL (54.27 mmol) of 12N aqueous ammonia solution and 2.32 g (43.41mmol) of NH₄Cl to a solution of 3 g (21.7 mmol) ofbicyclo[3.3.1]nonan-9-one in 40 mL of EtOH. Stir the reaction mixturefor 18 h at 50° C. Then add 5 mL of 12N aqueous ammonia solution andheat the mixture again for 4 h at 50° C. Cool the solution to RT thendistribute in 100 mL of a 1:1 mixture of ether/1N aqueous soda solution.After extraction, wash the organic phase with 3×50 mL of water, dry overNa₂SO₄ and concentrate under reduced pressure. Take up the residueobtained in 50 mL of ether and then treat for 1 minute with a gentlestream of hydrogen chloride. Filter the hydrochloride thus obtained,wash with 20 mL of ether and distribute in 100 mL of a 1:1 mixture ofDCM/saturated aqueous solution of Na₂CO₃. Extract the aqueous phaseagain with 50 mL of DCM, then combine the organic phases, wash with 2×20mL of water and dry over Na₂SO₄. After concentration under reducedpressure, we obtain 1.88 g of 9-aminobicyclo[3.3.1]nonane-9-carbonitrilein the form of oil.

Yield=52%

2.2. N-(9-cyanobicyclo[3.3.1]non-9-yl)benzamide

Add a solution of 2.37 g (17.17 mmol) of potassium carbonate in 30 mL ofwater, then 1.37 mL (11.8 mmol) of benzoyl chloride, to a solution of1.88 g (11.45 mmol) of 9-aminobicyclo[3.3.1]nonane-9-carbonitrile in 20mL of THF. Stir the reaction mixture for 1 h at RT, then distribute in100 mL of a 1:1 mixture of DCM/water. Wash the organic phase with 50 mLof water, dry over Na₂SO₄ and concentrate under reduced pressure.Solidify the residue obtained in 100 mL of pentane giving, afterfiltration and washing with pentane, 2.81 g ofN-(9-cyanobicyclo[3.3.1]non-9-yl)benzamide in the form of white powder.

Yield=92%

M.p. (° C.)>200

2.3. 9-Aminobicyclo[3.3.1]nonane-9-carboxylic acid

Add 200 mL of a 12N HCl aqueous solution to a solution of 2.8 g (10.43mmol) of N-(9-cyanobicyclo[3.3.1]non-9-yl)benzamide in 80 mL of THF.Stir the solution for 20 h at RT—a white precipitate gradually appears.After filtering the precipitate on a frit and rinsing with 3×200 mL ofwater, we obtain 3.6 g of wet 9-benzoylaminobicyclo[3.3.1]nonane-9-carboxylic acid.

Dissolve 3 g (10.44 mmol) of 9-benzoylaminobicyclo[3.3.1]nonane-9-carboxylic acid in 200 mL of AcOH and 50 mL of 6NHCl aqueous solution, reflux the mixture for 18 h and then concentratepartially by distillation of 150 mL of solvent. After cooling, filterthe reaction mixture and distribute in 150 mL of a 1:2 mixture of 1N HClaqueous solution/ether. After extraction, concentrate the aqueous phaseand then treat it dropwise with a 12N aqueous solution of soda (NaOH) toadjust the pH to 5-6. Filter the amino acid thus precipitated, wash with3×50 mL of water and dry under reduced pressure, which gives 1.88 g of9-aminobicyclo[3.3.1]nonane-9-carboxylic acid in the form of whitecrystals.

Yield=98%

M.p. (° C.)>250.

2.4.9-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylicacid hydrochloride

According to the method described in example 1.8, starting from 400 mg(0.85 mmol) of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylicacid and 218 mg (1.19 mmol) of 9-aminobicyclo[3.3.1]nonane-9-carboxylicacid and after reverse-phase purification and lyophilization, we obtain220 mg of9-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylicacid hydrochloride in the form of white powder.

Yield=41%

M.p. (° C.): 197

M=C₃₅H₄₂ClN₃O₆=635; M+H=636

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.45 (s, 1H); 8.00 (d, 1H); 7.80 (d,1H); 7.30 (t, 2H); 7.25 (s, 1H); 7.05 (d, 1H); 6.95 (dd, 1H); 6.70 (d,1H); 3.85 (t, 2H); 3.50 (s, 6H); 3.05 (m, 2H); 2.70 (s, 6H); 2.2-1.4 (m,16H).

EXAMPLE 32-({[6-{4-Chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride Compound No. 15 3.1. Ethyl6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate

Add 88 mg (0.87 mmol) of 1-methyl-3-hydroxypyrrolidine, 246 mg (1.09mmol) of triphenylphosphine and 0.01 mL (0.07 mmol) of TEA to a solutionof 300 mg (0.72 mmol) of ethyl6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylatein 2.5 mL of anhydrous THF cooled to 0° C. and placed under argon. Afterdissolution, add dropwise, at 0° C., a solution of 0.24 mL (1.09 mmol)of DIAD in 2.5 mL of anhydrous THF. Bring the reaction mixture to RT,stir for 18 h, then take up in 50 mL of EtOAc. Wash the organic phasesuccessively with 20 mL of a saturated aqueous solution of sodiumbicarbonate (NaHCO₃) then 20 mL of water. After drying over Na₂SO₄ andconcentration under reduced pressure, purify the residue obtained bysilica gel column chromatography, eluting with a DCM/methanol gradientfrom 0 to 20% of methanol. After concentration under reduced pressure,we obtain 250 mg of ethyl6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylatein the form of oil.

Yield=70%

3.2.2-({[6-{4-Chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 1.8 respectively, starting from 250 mg (0.5 mmol) ofethyl6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylateand 100 mg (0.51 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain160 mg of2-({[6-{4-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid in the form of white powder.

Yield=47%

M.p. (° C.)=215

M=C₃₆H₄₀ClN₃O₆=645; M+H=646

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.40 (s, 1H); 8.00 (d, 1H); 7.85 (d,1H); 7.35 (m, 2H); 7.05 (dd, 1H); 6.95 (t, 1H); 6.65 (d, 2H); 4.90 (m,1H); 3.80 (m, 2H); 3.50 (s, 6H); 3.15 (m, 2H); 2.85 (m, 3H); 2.55 (s,2H); 2.2-1.6 (m, 14H).

EXAMPLE 42-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride Compound No. 18

Methyl 6-bromo-5-hydroxy-2-pyridine carboxylate is synthesized accordingto a method already described in the literature (J. Org. Chem., 1996,4623-4633).

4.1. 2-(benzyloxy)-1-chloro-4-iodobenzene

A suspension of 300 g (1179 mmol) of 2-chloro-5-iodophenol and 140 mL(1179 mmol) of benzyl bromide and 195.5 g (1415 mmol) of anhydrouspotassium carbonate in 1.2 L of anhydrous DMF is stirred for 5 h at 70°C. and then cooled to RT. The reaction mixture is then distributed in 3L of a 2:1 ether/water mixture. The organic phase is washed with 2×1 Lof water, dried over Na₂SO₄, concentrated under reduced pressure and theresidue obtained is solidified in pentane. We thus obtain 376 g of2-(benzyloxy)-1-chloro-4-iodobenzene in the form of beige powder.

Yield=92%

M.p. (° C.)=72.

4.2. [3-(Benzyloxy)-4-chlorophenyl]boronic acid

Add dropwise 374 mL (748 mmol) of a solution of iPrMgCl 2N in THF to asolution of 198 g (575 mmol) of 2-(benzyloxy)-1-chloro-4-iodobenzene in1.2 L of anhydrous THF under argon and stirred at −50° C., maintainingthe temperature between −40 and −50° C. Allow the reaction mixture toreturn to −10° C. and continue stirring for 1 h. Then add 172 mL (748mmol) of triisopropyl borate and leave the reaction mixture to returnslowly to RT. After stirring for 2 h, treat the mixture with 1 L ofaqueous solution of HCl 5N, then extract with ether (2×600 mL). Wash theorganic phase with 2×1 L of water, dry over Na₂SO₄ then concentrateunder reduced pressure. Solidify the residue obtained in pentane, filteron a frit and wash with pentane. We thus obtain 113 g of[3-(benzyloxy)-4-chlorophenyl]boronic acid in the form of a white solid.

Yield=76%

M.p. (° C.)=148 (decomposition).

4.3. Methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-hydroxypyridine-2-carboxylate

Stir a solution of 37 g (163 mmol) of methyl6-bromo-5-hydroxy-2-pyridine carboxylate and 51 g (196 mmol) of[3-(benzyloxy)-4-chlorophenyl]boronic acid in 300 mL of anhydrous DMFfor 15 min while bubbling with argon, then add 63.8 g (196 mmol) ofanhydrous caesium carbonate and 5 g (4.33 mmol) of Pd(PPh₃)₄. Stir thereaction mixture for 10 h at 90° C. under argon, cool to RT, thendistribute in 1 L of ether/EtOAc 1:1 mixture and 1 L of a 0.5N aqueousHCl solution. Extract the aqueous phase again with 500 mL of EtOAc/ether1:1 mixture. Combine the organic phases and wash with 4×500 mL of water.After drying over Na₂SO₄ and concentration under reduced pressure, takeup the precipitate with 500 mL of a 7:3 mixture of pentane/DCM, filterand wash with pentane. We thus obtain 32 g of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-hydroxypyridine-2-carboxylate in theform of yellow ochre powder.

Yield=53%

M.p. (° C.)=202

4.4. Methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate

Add 17.7 mL (126 mmol) of TEA to a mixture of 38.8 g (105 mmol) ofmethyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-hydroxypyridine-2-carboxylatein 200 mL of DCM. The mixture dissolves gradually and is cooled to −5°C. under argon. Add, dropwise, 19.42 mL (115.4 mmol) oftrifluoromethanesulphonic anhydride, maintaining the temperature at 0°C. After 3 h at 0° C., take up the reaction mixture in 300 mL of DCM andwash with 2×200 mL of water, dry over Na₂SO₄, then concentrate underreduced pressure. Purify the residue obtained by chromatography on asilica column, eluting with a pentane/EtOAc gradient from 0 to 30% ofEtOAc. After concentration under reduced pressure, we obtain 47.5 g ofmethyl6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylatein the form of white crystals.

Yield=90%

M.p. (° C.)=89.

4.5. Methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyridine-2-carboxylate

Stir a solution of 25 g (48.8 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylateand 8.8 g (64.8 mmol) of 2-methylphenylboronic acid in 200 mL ofanhydrous DMF for 15 min while bubbling with argon, then add 12.7 g (60mmol) of anhydrous potassium phosphate (K₃PO₄) and 5.76 g (5 mmol) ofPd(PPh₃)₄ and stir the reaction mixture for 18 h at 90° C. under argon.Then distribute the reaction mixture at RT in 600 mL of ether/EtOAc 1:1mixture and 600 ml of water. After extraction, extract the aqueous phaseagain with 100 mL of EtOAc, combine the organic phases and wash with4×300 mL of water, dry over Na₂SO₄, then concentrate under reducedpressure. Purify the residue obtained by silica gel columnchromatography, eluting with a heptane/EtOAc gradient from 0 to 20% ofEtOAc. After concentration under reduced pressure, we obtain 18 g ofmethyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyridine-2-carboxylatein the form of oil.

Yield=81%

4.6. Methyl6-(4-chloro-3-hydroxy]phenyl)-5-(2-methylphenyl)pyridine-2-carboxylate

Add dropwise, in 1 h 30 min, 85.6 mL (85.6 mmol) of a 1N solution ofboron tribromide in DCM to a solution of 19 g (42.8 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyridine-2-carboxylatein 70 mL of anhydrous DCM cooled under argon to −70° C., maintaining thetemperature at −65° C. After stirring for 2 h at −70° C., add dropwise20 mL (520 mmol) of anhydrous methanol, maintaining the temperature at−65° C. Bring the reaction mixture to RT, then concentrate under reducedpressure. Take up the residue in 100 mL of toluene and concentrateagain. Repeat the operation two more times. Take up the residue obtainedin 100 mL of methanol and cool under argon at 0° C., then add dropwise 9mL (128 mmol) of thionyl chloride. Stir the reaction mixture for 48 h atRT, then concentrate under reduced pressure. Take up the residueobtained in 200 mL of EtOAc, cool to 0° C. and treat with 300 mL of asaturated aqueous solution of NaHCO₃. After extraction, extract theaqueous phase again with 100 mL of EtOAc. Combine the organic phases,wash with 100 mL of water, dry over Na₂SO₄ and concentrate under reducedpressure. Purify the residue by silica gel column chromatography,eluting with a heptane/EtOAc gradient from 0 to 30% of EtOAc. Afterconcentration under reduced pressure, we obtain 14.7 g of methyl6-(4-chloro-3-hydroxyphenyl)-5-(2-methylphenyl)pyridine-2-carboxylate inthe form of white powder.

Yield=97%

M.p. (° C.)=190

4.7. Methyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate

According to the method described in example 1.6, starting from 5.4 g(15.26 mmol) of methyl6-(4-chloro-3-hydroxyphenyl)-5-(2-methylphenyl)pyridine-2-carboxylate,9.95 g (30.53 mmol) of caesium carbonate and 2.9 g (18.3 mmol) of3-chloro-N,N-dimethylpropan-1-amine hydrochloride in 60 mL of DMF, weobtain 6 g of methyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylatein the form of oil.

Yield=90%

4.8.2-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 1.8 respectively, starting from 4.65 g (10.6 mmol) ofmethyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylateand 2.38 g (12.18 mmol) of 2-aminoadamantane-2-carboxylic acid, weobtain 4.1 g of2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride in the form of white powder.

Yield=54%

M.p. (° C.): 224.

M=C₃₅H₄₀ClN₃O₄=601; M+H=602

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.50 (s, 1H); 8.05 (d, 1H); 7.90 (d,1H); 7.25 (m, 5H); 7.10 (dd, 1H); 6.95 (dd, 1H); 3.80 (m, 2H); 3.1 (m,2H); 2.75 (s, 6H); 2.60 (s, 2H); 1.90 (s, 3H); 2.2-1.6 (m, 14H).

EXAMPLE 52-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride Compound No. 23 5.1. Methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate

Stir a solution of 500 mg (1 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate,0.1 mL (1.1 mmol) of 2-pyrrolidinone and 450 mg (1.4 mmol) of caesiumcarbonate in 10 mL of anhydrous 1,4-dioxan for 10 minutes while bubblingwith argon, then add 9 mg (0.01 mmol) of Pd₂(dba)₃ and 17 mg (0.03 mmol)of Xantphos and heat the reaction mixture for 6 h at 70° C. whilestirring. Then distribute the mixture in 100 mL of ether/EtOAc 1:1mixture and 50 mL of a saturated aqueous solution of NH₄Cl. Afterextraction, wash the organic phase with 2×50 mL of water, dry overNa₂SO₄ and concentrate under reduced pressure. Purify the residueobtained by silica gel column chromatography, eluting with aheptane/EtOAc gradient from 0 to 30% of EtOAc. After concentration underreduced pressure, we obtain 293 mg of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylatein the form of oil.

Yield=67%.

5.2. Methyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate

According to the debenzylation/O-alkylation steps described in examples4.6 and 1.6 respectively, starting from 511 mg (1.17 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate,we obtain 391 mg of methyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylatein the form of oil.

Yield=77%

5.3.2-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 1.8 respectively, starting from 391 mg (0.91 mmol) ofmethyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylateand 265 mg (1.36 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain241 mg of2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride in the form of white powder.

Yield=39%

M.p. (° C.): 199

M=C₃₂H₃₉ClN₄O₅=594; M+H=595

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.40 (s, 1H); 8.05 (t, 2H); 7.55 (d,1H); 7.50 (s, 1H); 7.20 (dd, 1H); 4.15 (t, 2H); 3.65 (t, 2H); 2.75 (s,6H); 2.55 (s, 2H); 2.2-1.6 (m, 20H).

EXAMPLE 62-{[(2′-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylicacid hydrochloride Compound No. 27 6.1. Methyl2′-[3-(benzyloxy)-4-chlorophenyl]-2,3′-bipyridine-6′-carboxylate

Stir a suspension of 0.5 g (1 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate,0.44 g (1.2 mmol) of 2-tri-n-butylstannylpyridine and 42 mg (1 mmol) ofanhydrous lithium chloride in 2 mL of anhydrous DMF for 10 min whilebubbling with argon, then add 9.5 mg (0.05 mmol) of CuI, 45 mg (0.05mmol) of Pd₂(dba)₃ and 27 mg (0.05 mmol) of PdCl₂ (dppf) and then heatthe reaction mixture to 90° C. After stirring for 5 h at 90° C., coolthe mixture to RT, take up in 30 ml of EtOAc, treat and stir for 15minutes with 30 mL of a 5 wt. % aqueous solution of potassium fluoride.Then filter the two-phase mixture on a bed of celite, and rinse thecelite with 30 mL of EtOAc. Wash the organic phase with 4×60 mL ofwater, dry over Na₂SO₄ and concentrate at reduced pressure. Purify theresidue obtained by chromatography on a silica column, eluting with atoluene/EtOAc gradient from 0 to 15% of EtOAc. After concentration underreduced pressure, we obtain 240 mg of methyl2′-[3-(benzyloxy)-4-chlorophenyl]-2,3′-bipyridine-6′-carboxylate in theform of oil.

Yield=55%

6.2. Methyl2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate

According to the debenzylation/O-alkylation steps described in examples4.6 and 1.6 respectively, starting from 680 mg (1.58 mmol) of methyl2′-[3-(benzyloxy)-4-chlorophenyl]-2,3′-bipyridine-6′-carboxylate, weobtain 580 mg of methyl2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylatein the form of oil.

Yield=86%

6.3.2-{[(2′-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylicacid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 1.8 respectively, starting from 581 mg (1.36 mmol) ofmethyl2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylateand 365 mg (1.87 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain435 mg of2-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylicacid hydrochloride in the form of white powder.

Yield=48%

M.p. (° C.): 209

M=C₃₃H₃₇ClN₄O₄=588; M+H=589

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.55 (s, 1H); 8.65 (s, 1H); 8.50 (s,1H); 8.25 (d, 1H); 8.10 (d, 1H); 7.80 (t, 1H); 7.40 (dd, 1H); 7.35 (d,2H); 7.25 (s, 1H); 6.80 (d, 1H); 3.95 (t, 2H); 3.15 (m, 2H); 2.75 (s,3H); 2.70 (s, 3H); 2.60 (s, 2H); 2.2-1.6 (m, 14H).

EXAMPLE 72-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride Compound No. 22 7.1. Methyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylate

According to the debenzylation/O-alkylation steps described in examples4.6 and 1.6 respectively, starting from 625 mg (1.35 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-chlorophenyl)pyridine-2-carboxylate,we obtain 173 mg of methyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylatein the form of oil.

Yield=28%

7.2.2-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 1.8 respectively, starting from 290 mg (0.63 mmol) ofmethyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylateand 184 mg (0.94 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain120 mg of2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride in the form of white powder.

Yield=29%

M.p. (° C.): 214

M=C₃₄H₃₇Cl₂N₃O₄=621; M+H=622

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.50 (s, 1H); 8.10 (d, 1H); 8.00 (d,1H); 7.45 (m, 2H); 7.40 (d, 2H); 7.35 (d, 1H); 7.20 (dd, 1H); 6.90 (dd,1H); 3.90 (m, 2H); 3.15 (m, 2H); 2.75 (s, 6H); 2.60 (s, 2H); 2.2-1.6 (m,14H).

EXAMPLE 81-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride Compound No. 34

According to the saponification/peptide coupling steps described inexamples 1.7 and 1.8 respectively, starting from 465 mg (1.06 mmol) ofmethyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate(example 4.7) and 174 mg (1.22 mmol) of 2-aminocyclohexane-2-carboxylicacid, we obtain 330 mg of1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride in the form of white powder.

Yield=53%

M.p. (° C.)=146-150

M=C₃₁H₃₆ClN₃O₄=549; M+H=550

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.5 (s, 1H); 8.40 (s, 1H); 8.05 (d,1H); 7.90 (d, 1H); 7.35 (d, 1H); 7.25 (m, 5H); 7.05 (dd, 1H); 3.80 (m,2H); 3.1 (m, 2H); 2.75 (s, 6H); 1.75 (s, 3H); 2.2-1.6 (m, 12H).

EXAMPLE 9cis-1-({[6-{4-Chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic acid hydrochloride Compound No. 147

Add successively, under argon and at RT, 127 mg (1.1 mmol) ofN-hydroxysuccinimide and 211 mg (1.1 mmol) of EDC.HCl to a mixture of490 mg (1 mmol) of6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylicacid hydrochloride in 5 mL of anhydrous DMF. After stirring for 18 h,add successively to the (bright yellow, clear) reaction mixture, 0.9 mL(5.4 mmol) of DIEA and 215 mg (1.1 mmol) ofcis-1-amino-4-hydroxycyclohexane carboxylic acid (J. Chem. Soc., PerkinTrans. 1 (1999) pp. 3375-3379). Continue stirring for 18 h at RT, thenconcentrate the reaction mixture under reduced pressure. Then treat theresidue obtained for 18 h at RT with 7 mL (7 mmol) of 1N HCl, thenconcentrate under reduced pressure. Purify the residue by HPLC on acolumn of RP18, eluting with a 10⁻²N HCl/acetonitrile gradient from 0%to 100% of acetonitrile. After lyophilization, we obtain 350 mg ofcis-1-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=55%

M.p. (° C.)=168

M=C₃₃H₄₀ClN₃O₅=565; M+H=566

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.55 (s, 1H); 8.05 (d, 1H); 7.90 (d,1H); 7.25 (m, 6H); 6.90 (dd, 1H); 4.65 (sl, 1H); 3.90 (m, 2H); 3.50 (m,1H); 3.10 (m, 2H); 2.95 (q, 4H); 2.30 (m, 2H); 2.05 (m, 2H); 1.90 (s,3H); 1.80 (m, 4H); 1.35 (m, 2H); 1.10 (t, 6H)

EXAMPLE 103-[({4″-Chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoicacid hydrochloride Compound No. 2810.1.2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Stir a suspension of 20 g (67.2 mmol) of2-benzyloxy-4-bromo-1-chlorobenzene, 28 g (94 mmol) of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane and 26.4 g(26.9 mmol) of potassium acetate in 280 mL of anhydrous DMSO for 10minutes under argon, then add 2.46 g (3.4 mmol) of PdCl₂ (dppf) and heatfor 1 h at 110° C. After distributing in 1 L of a 1:1 ether/watermixture and filtering on a bed of celite, wash the organic phase with100 mL of water, dry over Na₂SO₄, then concentrate under reducedpressure. Purify the residue obtained by silica gel columnchromatography, eluting with a heptane/EtOAc gradient from 0 to 10% ofEtOAc. After concentration under reduced pressure, we obtain 17.5 g of2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein the form of oil.

Yield=74%.

10.2. Methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate

Stir a solution of 4.84 g (14.2 mmol) of methyl 3-bromo-4-iodobenzoate(J. Med. Chem., 1999, 42, 4088) and 3.88 g (21.29 mmol) of2,6-dimethoxyphenyl boronic acid in 120 mL of DMF and 14.2 mL of a 2Maqueous solution of caesium carbonate for 15 minutes under argon, thenadd 984 mg (0.85 mmol) of Pd(PPh₃)₄ and heat for 2.5 h at 85° C. Afterconcentration under reduced pressure, distribute the residue obtained in600 mL of a 1:1 DCM/water mixture. Wash the organic phase with 100 mL ofwater, dry over MgSO₄ and concentrate at reduced pressure. Purify theresidue obtained by silica gel column chromatography, eluting with aheptane/EtOAc gradient from 0 to 10% of EtOAc. After concentration underreduced pressure, we obtain 2.79 g of methyl2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate in the form of oil.

Yield=56%

10.3. Methyl3″-(benzyloxy)-4″-chloro-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate

According to the method described in example 10.2, starting from 2.79 g(7.94 mmol) of methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate and3.28 g (9.53 mmol) of2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,we obtain 1.75 g of methyl3″-(benzyloxy)-4″-chloro-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylatein the form of oil.

Yield=45%

10.4. Methyl4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate

According to the debenzylation/O-alkylation steps described in examples4.6 and 1.6 respectively, starting from 1.75 g (3.58 mmol) of methyl3″-(benzyloxy)-4″-chloro-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate,we obtain 900 mg of methyl4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylatein the form of oil.

Yield=52%

10.5.4″-Chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylicacid

According to the method described in example 1.7, starting from 900 mg(1.86 mmol) of methyl4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate,we obtain 700 mg of4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylicacid in the form of a pinkish solid.

Yield=82%

M.p. (° C.)=230.

10.6.3-[({4″-Chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoicacid hydrochloride

Add 141 mg (0.87 mmol) of CDI to a solution of 315 mg (0.67 mmol) of4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylicacid in 7 mL of anhydrous THF, and stir the reaction mixture at 55° C.for 1 h under argon. Add 70 mg (0.43 mmol) of carbonyl-1,1′-diimidazoleand continue the reaction for 1 h at 50° C. Then add a suspension of 97mg (0.74 mmol) of racemic 3-amino-4-methylpentanoic acid in a mixture of4 mL of THF and 0.8 mL of DMF and continue stirring for 15 h at 55° C.After concentration under reduced pressure, distribute the residueobtained in 30 mL of a 2:1 DCM/water mixture. Wash the organic phasewith 10 mL of water, dry over magnesium sulphate (MgSO₄) and concentrateunder reduced pressure. Purify the residue obtained by silica gel columnchromatography, eluting with a DCM/methanol gradient from 0 to 5% ofmethanol. After concentration under reduced pressure, solidify theresidue in ether, filter on a frit and wash with ether. We thus obtain91 mg of3-[({4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoicacid hydrochloride in the form of white powder.

Yield=23%

M.p. (° C.)=152

M=C₃₂H₃₉ClN₂O₆=582; M+H=583

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.3 (d, 1H); 7.75 (d, 1H); 7.7 (s, 1H);7.2 (m, 3H); 6.7 (m, 2H); 6.55 (d, 2H); 4.1 (q, 1H) 3.8 (t, 2H); 3.5 (s,6H); 2.45 (m, 4H); 2.3 (s, 6H) 1.8 (m, 3H); 0.9 (d, 6H).

EXAMPLE 113-({[5-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride Compound 29 11.1. Methyl5-[3-(benzyloxy)-4-chlorophenyl]-6-oxo-1,6-dihydropyridine-3-carboxylate

Stir a solution of 4 g (14.35 mmol) of methyl5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate and 6.42 g (18.64 mmol)of2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein a mixture of 160 mL of dimethoxyethane (DME), 80 mL of EtOH and 120mL of a saturated aqueous solution of NaHCO₃ for 15 minutes under argon,then add 662 mg of Pd(PPh₃)₄ and heat the reaction mixture for 4 h 30min at 90° C. After concentration under reduced pressure, distribute theresidue obtained in a mixture of 200 mL of DCM and 10 mL of water.Extract the aqueous phase again with 100 mL of DCM, combine the organicphases, dry over MgSO₄, filter and concentrate under reduced pressure.Purify the residue obtained by silica gel column chromatography, elutingwith a DCM/methanol gradient from 0 to 2% of methanol. Afterconcentration under reduced pressure, solidify the residue in a 5/95methanol/ether mixture, then filter and wash with ether. We thus obtain1.99 g of methyl5-[3-(benzyloxy)-4-chlorophenyl]-6-oxo-1,6-dihydropyridine-3-carboxylatein the form of a beige solid.

Yield=40%

M.p. (° C.): 190

11.2. Methyl5-[3-(benzyloxy)-4-chlorophenyl]-6-{[(trifluoromethyl)sulphonyl]oxy}nicotinate

According to the method described in example 4.4, starting from 1.99 g(5.38 mmol) of methyl5-[3-(benzyloxy)-4-chlorophenyl]-6-oxo-1,6-dihydropyridine-3-carboxylateand 2.26 ml (13.45 mmol) of trifluoromethanesulphonic anhydride, weobtain 1.6 g of methyl5-[3-(benzyloxy)-4-chlorophenyl]-6-{[(trifluoromethyl)sulphonyl]oxy}nicotinatein the form of oil.

Yield=60%

11.3. Methyl5-[3-(benzyloxy)-4-chlorophenyl]-6-(2-methylphenyl)nicotinate

According to the method described in example 4.5, starting from 1.5 g(2.99 mmol) of methyl5-[3-(benzyloxy)-4-chlorophenyl]-6-{[(trifluoromethyl)sulphonyl]oxy}nicotinateand of 508 mg (3.74 mmol) of 2-methylphenyl boronic acid, we obtain 1.26g of methyl5-[3-(benzyloxy)-4-chlorophenyl]-6-(2-methylphenyl)nicotinate in theform of oil.

Yield=95%

11.4. Methyl5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)nicotinate

According to the debenzylation/O-alkylation steps described in examples4.6 and 1.6 respectively, starting from 1.26 g (2.84 mmol) of methyl5-[3-(benzyloxy)-4-chlorophenyl]-6-(2-methylphenyl)nicotinate, we obtain843 mg of methyl5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)nicotinatein the form of oil.

Yield=68%

11.5.3-({[5-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 10.6 respectively, starting from 835 mg (1.90 mmol) ofmethyl5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)nicotinateand 258 mg (1.97 mmol) of racemic 3-amino-4-methylpentanoic acid, weobtain 130 mg of3-({[5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride in the form of a white solid.

Yield=13%

M.p. (° C.)=139

M=C₃₀H₃₆ClN₃O₄=537; M+H=538

¹H NMR (ppm, d6-DMSO, 400 MHz): 9.05 (d, 1H); 9.5 (d, 1H); 9.25 (d, 1H);8.3 (d, 1H); 7.3 (d, 1H) 7.15 (d, 1H); 7.15 (m, 4H); 4.25 (m, 1H); 3.8(t, 2H); 2.65 (t, 2H); 2.45 (s, 6H) 1.95 (s, 3H); 1.85 (m, 5H); 0.90 (d,6H).

EXAMPLE 122-({[6-[3-[3-(Dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride Compound No. 43 12.1. 2-iodo-5-nitrophenol

Add, dropwise, a solution of 20.7 g (300 mmol) of sodium nitrite (NaNO₂)in 100 mL of water to a solution of 30.81 g (200 mmol) of2-amino-5-nitrophenol in a mixture of 500 mL of sulphuric acid at 30 wt.% and 500 mL of DMSO cooled to 5° C., maintaining the temperature at 5°C. After 30 min at 5° C., add dropwise a solution of 90 g (600 mmol) ofsodium iodide in 100 mL of water, then bring the reaction mixture up toRT. After stirring for 2 h, distribute the reaction mixture in 2 L of amixture of ether/aqueous solution at 10 wt. % of sodium bisulphite 1:1.Extract the aqueous phase again with 200 mL of ether, combine theorganic phases and wash with 3×1 L of water, then dry over Na₂SO₄. Afterconcentration under reduced pressure, purify the residue obtained bysilica gel column chromatography, eluting with a cyclohexane/EtOAcgradient from 0 to 10% of EtOAc. After concentration under reducedpressure, we obtain 39.8 g of 2-iodo-5-nitrophenol in the form of abrown solid.

Yield=75%

M.p. (° C.)=150

12.2. 2-(benzyloxy)-1-iodo-4-nitrobenzene

According to the method described in example 4.1., starting from 20.8 g(78.5 mmol) of 2-iodo-5-nitrophenol and 9.3 mL (78.5 mmol) of benzylbromide, we obtain 25.2 g of 2-(benzyloxy)-1-iodo-4-nitrobenzene in theform of oil.

Yield=90%

12.3. 2-(benzyloxy)-4-nitro-1-(trifluoromethyl)benzene

Add 10.4 mL (70.18 mmol) of trifluoromethyltrimethylsilane to a mixtureof 4.08 g (70.2 mmol) of anhydrous potassium fluoride and 13.36 g (70.18mmol) of anhydrous CuI and 19.17 g (54 mmol) of2-(benzoxy)-1-iodo-nitrobenzene in 77 mL of anhydrous NMP, and heat thereaction mixture for 18 h at 45° C. under argon. Distribute thesuspension at RT in 1 L of a 1:1 ether/water mixture, then wash theorganic phase with 4×300 mL of water, dry over Na₂SO₄, and concentrateunder reduced pressure. We thus obtain 15 g of2-(benzyloxy)-4-nitro-1-(trifluoromethyl)benzene in the form of oil.

Yield=94%

12.4. 3-(benzyloxy)-4-(trifluoromethyl)aniline

Add 14.1 g (252 mmol) of iron filings to a mixture of 15 g (50.3 mmol)of 2-(benzyloxy)-4-nitro-1-(trifluoromethyl)benzene in 200 mL of EtOH,10 mL of AcOH and 100 mL of water, then stir the reaction mixturevigorously at 70° C. for 20 minutes. After cooling to RT, slowly add thereaction mixture to a mixture of 300 mL of ether and 1 L of a saturatedaqueous solution of Na₂CO₃. After neutralizing, extract the aqueousphase again with 2×100 mL of ether. Combine the organic phases, washwith 100 mL of water, dry over calcium chloride and concentrate underreduced pressure. Purify the residue obtained by silica gel columnchromatography, eluting with a pentane/EtOAc gradient from 0 to 50% ofEtOAc. After concentration under reduced pressure, we obtain 8.1 g of3-(benzyloxy)-4-(trifluoromethyl)aniline in the form of oil.

Yield=60%

12.5. 2-(benzyloxy)-4-iodo-1-(trifluoromethyl)benzene

According to the method described in example 12.1., starting from 8 g(30 mmol) of 3-(benzyloxy)-4-(trifluoromethyl)aniline, we obtain 8 g of2-(benzyloxy)-4-iodo-1-(trifluoromethyl)benzene in the form of oil.

Yield=70%

12.6. [3-(Benzyloxy)-4-(trifluoromethyl)phenyl]boronic acid

According to the method described in example 4.2, starting from 8 g(21.2 mmol) of 2-(benzyloxy)-4-iodo-1-(trifluoromethyl)benzene, 11.1 mL(22.2 mmol) of iPrMgCl and 5 mL (21.6 mmol) of triisopropyl borate, weobtain 4.95 g of [3-(benzyloxy)-4-(trifluoromethyl)phenyl]boronic acidin the form of oil.

Yield=79%

12.7. Methyl6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylate

According to the method described in example 4.3, starting from 4.95 g(16.7 mmol) of [3-(benzyloxy)-4-(trifluoromethyl)phenyl]boronic acid and3.88 g (16.72 mmol) of methyl 6-bromo-5-hydroxypyridine-2-carboxylate,we obtain 4.38 g of methyl6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylatein the form of a white solid.

Yield=65%

M.p. (° C.)=82

12.8. Methyl6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate

According to the triflate/Suzuki coupling steps described in examples4.4 and 4.5 respectively, starting from 4.38 g (10.9 mmol) of methyl6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylateand 1.8 g (13.1 mmol) of 2-methylphenylboronic acid, we obtain 4.63 g ofmethyl6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylatein the form of a white solid.

Yield=89%

M.p. (° C.)=226

12.9. Methyl6-[3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate

According to the debenzylation/O-alkylation steps described in examples4.6 and 1.6 respectively, starting from 2.57 g (5.38 mmol) of methyl6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate,we obtain 2.26 g of methyl6-[3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylatein the form of a white solid.

Yield=89%

M.p. (° C.)=142

12.10.2-({[6-[3-[3-(Dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 1.8 respectively, starting from 565 mg (1.19 mmol) ofmethyl6-[3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylateand 256 mg (1.31 mmol) of 2-amino-adamantane-2-carboxylic acid, weobtain 440 mg of2-({[6-[3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride in the form of white powder.

Yield=55%

M.p. (° C.)=231

M=C₃₆H₄₀F₃N₃O₄=634; M+H=635

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.50 (s, 1H); 8.10 (d, 1H); 7.95 (d,1H); 7.55 (d, 1H); 7.25 (m, 5H); 7.10 (d, 1H); 3.90 (m, 2H); 3.05 (m,2H); 2.70 (s, 6H); 2.60 (s, 2H); 2.05 (m, 7H); 1.90 (s, 3H); 1.65 (m,7H).

EXAMPLE 131-{[(3-Chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride Compound No. 55 13.1. Methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate

Stir a solution of 5 g (10 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylateand 2.78 g (11 mmol) of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane in 50 mL ofanhydrous 1,4-dioxan for 15 min while bubbling with argon, then add 2.93g (30 mmol) of anhydrous potassium acetate and 0.37 g (0.45 mmol) ofPdCl₂(dppf) and heat the reaction mixture for 26 h at 80°. Thendistribute the reaction mixture in 100 mL of EtOAc/brine 1:1 mixture.Dry the organic phase over Na₂SO₄, filter, and then concentrate underreduced pressure. Purify the residue obtained by chromatography on asilica column, eluting with a cyclohexane/EtOAc gradient from 0 to 20%of EtOAc. After concentration under reduced pressure, we obtain 3.2 g ofmethyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylatein the form of a wax.

Yield=67%

13.2. Methyl2′-[3-(benzyloxy)-4-chlorophenyl]-3-chloro-2,3′-bipyridine-6′-carboxylate

Stir a solution of 850 mg (1.77 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylateand 524 mg (3.54 mmol) of 2,3-dichloropyridine in a mixture of 4 mL ofDME and 2 mL of water for 15 minutes under argon, then add successively734 mg (5.32 mmol) of K₂CO₃ and 61 mg (0.05 mmol) of Pd(PPh₃)₄ and heatthe reaction mixture for 4 h at 85° C. Then distribute the reactionmixture between 10 mL of EtOAc and 10 mL of brine. Dry the organic phaseover Na₂SO₄, filter, and then concentrate under reduced pressure. Purifythe residue obtained on a silica column, eluting with acyclohexane/EtOAc gradient from 0 to 20% of EtOAc. After concentrationunder reduced pressure, we obtain 237 mg of methyl2′-[3-(benzyloxy)-4-chlorophenyl]-3-chloro-2,3′-bipyridine-6′-carboxylatein the form of oil.

Yield=28%

13.3. Methyl3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate

According to the debenzylation/O-alkylation steps described in examples4.6 and 1.6 respectively, starting from 360 mg (0.77 mmol) of methyl2′-[3-(benzyloxy)-4-chlorophenyl]-3-chloro-2,3′-bipyridine-6′-carboxylate,we obtain 130 mg of methyl3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylatein the form of oil.

Yield=37%

13.4.1-{[(3-Chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 1.8 respectively, starting from 130 mg (0.28 mmol) ofmethyl3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylateand 44 mg (0.31 mmol) of 2-aminocyclohexanecarboxylic acid, we obtain120 mg of1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=70%

M.p. (° C.)=140

M=C₂₉H₃₂Cl₂N₄O₄=570; M+H=571

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.45 (s, 1H); 8.65 (d, 1H); 8.45 (s,1H); 8.10 (s, 2H); 7.95 (d, 1H); 7.50 (dd, 1H); 7.35 (d, 1H); 7.25 (d,1H); 6.90 (dd, 1H); 3.95 (t, 2H); 3.15 (m, 2H); 2.80 (d, 6H); 2.20 (m,4H); 1.80 (t, 2H); 1.70-1.2 (m, 6H).

EXAMPLE 14(3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride Compound No. 72 14.1. Methyl6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridine-2-carboxylate

According to the debenzylation/O-alkylation steps described in examples4.6 and 1.6 respectively, starting from 743 mg (1.55 mmol) of6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-chloro-5-methylphenyl)pyridine-2-carboxylate,we obtain 530 mg of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridine-2-carboxylatein the form of oil.

Yield=72%

14.2.(3S)-3-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 9 respectively, starting from 385 mg (0.84 mmol) of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridine-2-carboxylateand 130 mg (1 mmol) of (3S)-3-amino-4-methylpentanoic acid (J. Org.Chem., 1999, 6411-6417), we obtain 333 mg of(3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride in the form of white powder.

Yield=67%

M.p. (° C.)=157

[α]_(D) ²²=−18°; (c=0.1; MeOH)

M=C₃₀H₃₅Cl₂N₃O₄=571; M+H=572

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.60 (dd, 1H); 8.10 (d, 1H); 7.95 (d,1H); 7.40-7.15 (m, 5H); 6.90 (d, 1H); 4.15 (m, 1H); 3.90 (m, 2H); 3.15(t, 2H); 2.75 (s, 6H); 2.55 (t, 2H); 2.25 (d, 3H (conformers)); 2.10 (m,2H); 1.90 (m, 1H); 0.85 (dd, 6H (conformers)).

EXAMPLE 151-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride Compound No. 66 15.1. Methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2,4-dimethylphenyl)pyridine-2-carboxylate

According to the method described in example 4.5, Suzuki couplingeffected between 1 g (2 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylateand 418 mg (2.8 mmol) of 2,4-dimethylphenylboronic acid leads to 820 mgof methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2,4-dimethylphenyl)pyridine-2-carboxylatein the form of oil.

Yield=90%

15.2.6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridine-2-carboxylicacid hydrochloride

According to the debenzylation/O-alkylation/saponification stepsdescribed in examples 4.6, 1.6 and 1.7 respectively, starting from 820mg (1.8 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2,4-dimethylphenyl)pyridine-2-carboxylate,we obtain 659 mg of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridine-2-carboxylicacid hydrochloride in the form of gum.

Yield=77%

15.3.1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride

According to the method described in example 1.8, peptide couplingeffected between 356 mg (0.75 mmol) of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridine-2-carboxylicacid hydrochloride and 113 mg (0.79 mmol) of2-aminocyclohexane-2-carboxylic acid leads to 160 mg of1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride in the form of white powder.

Yield=38%

M.p. (° C.)=158

M=C₃₂H₃₈ClN₃O₄=563; M+H=564

¹H NMR (ppm, d6-DMSO, 400 MHz): 12.45 (s, 1H); 10.40 (s, 1H); 8.45 (s,1H); 8.05 (d, 1H); 7.95 (d, 1H); 7.40 (d, 1H); 7.20 (s, 1H); 7.15 (s,2H); 2.75 (s, 6H); 7.10 (d, 1H); 7.05 (d, 1H); 3.90 (m, 2H); 3.20 (t,2H); 2.70 (s, 6H); 2.35 (s, 3H); 2.2-2.05 (m, 4H); 1.90 (s, 3H); 1.85(t, 2H); 1.75-1.30 (m, 6H).

EXAMPLE NO. 16(3S)-3-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoicacid hydrochloride Compound No. 117

According to the method described in example 9, peptide couplingeffected between 950 mg (2 mmol) of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridine-2-carboxylicacid hydrochloride and 412 mg (2.05 mmol) of tert-butyl(3S)-3-amino-4,4-dimethylpentanoate (J. Org. Chem., 1999, 64, 6411-6417)leads to 830 mg of(3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoicacid hydrochloride in the form of white powder.

Yield=70%

M.p. (° C.)=130

[α]_(D) ²²=−5°; (c=0.1; MeOH)

M=C₃₂H₄₀ClN₃O₄=565; M+H=566

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.09 (s, 1H); 8.2 (d, 1H); 7.85 (d,1H); 7.70 (d, 1H); 7.10 (d, 1H); 6.95 (d, 1H); 6.85 (m, 3H); 6.80 (t,1H); 4.10 (t, 1H); 3.65 (m, 2H); 2.95 (m, 2H); 2.50 (d, 6H); 2.40 (dd,1H); 2.30 (dd, 1H); 2.10 (s, 3H); 1.85 (m, 2H); 1.65 (s, 3H); 0.70 (d,9H, conformers).

EXAMPLE NO. 171-{[(3,5-Dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride Compound No. 65 17.1. Methyl2′-[3-(benzyloxy)-4-chlorophenyl]-3,5-dichloro-2,3′-bipyridine-6′-carboxylate

According to the method described in example 13.2, Suzuki-Myauracoupling effected between 4.4 g (9.17 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylateand 2.5 g (11 mmol) of 2-bromo-3,5-dichloropyridine leads to 3 g ofmethyl2′-[3-(benzyloxy)-4-chlorophenyl]-3,5-dichloro-2,3′-bipyridine-6′-carboxylatein the form of oil.

Yield=65%

17.2. Methyl3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3-bipyridine-6′-carboxylate

According to the debenzylation/O-alkylation steps described in examples4.6 and 1.6 respectively, starting from 3 g (6.2 mmol) of methyl2′-[3-(benzyloxy)-4-chlorophenyl]-3,5-dichloro-2,3′-bipyridine-6′-carboxylate,we obtain 1.8 g of methyl3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylatein the form of gum.

Yield=58%

17.3.1-{[(3,5-Dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride

According to the saponification/peptide coupling steps described inexamples 1.7 and 1.8 respectively, starting from 1.8 g (3.62 mmol) ofmethyl3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylateand 472 mg (3.3 mmol) of 2-aminocyclohexane-2-carboxylic acid, we obtain1.12 g of1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride in the form of white powder.

Yield=50%

M.p. (° C.)=165

M C₂₉H₃₁Cl₃N₄O₄=604; M+H=605

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.75 (s, 1H); 8.45 (s, 1H); 8.30 (d,1H); 8.15 (dd, 2H); 7.35 (d, 1H); 7.30 (s, 1H); 6.75 (dd, 1H); 4.00 (t,2H); 3.20 (m, 2H); 2.75 (d, 6H); 2.3-1.3 (m, 12H).

EXAMPLE NO. 181-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride Compound No. 75 18.1. Methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-[2-(diphenylmethylidene)hydrazino]pyridine-2-carboxylate

Put 2 g (4 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylatein 10 mL of anhydrous toluene in a screw-top bottle. To the solution,under argon, add successively 938 mg (4.78 mmol) of benzophenonehydrazone, 1.95 g (6 mmol) of caesium carbonate and 65 mg (0.08 mmol) ofPdCl₂ (dppf). Heat the reaction mixture for 3 h at 90° C. whilestirring, then distribute in 100 mL of ether/water 1:1 mixture. Dry theorganic phase over Na₂SO₄ and concentrate under reduced pressure. Purifythe residue obtained by silica gel column chromatography, eluting with aDCM/acetone gradient from 0 to 5% of acetone. After concentration underreduced pressure, we obtain 1.94 g of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-[2-(diphenylmethylidene)hydrazino]pyridine-2-carboxylatein the form of oil.

Yield=88%

18.2. Ethyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylate

Put 600 mg (1.08 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-[2-(diphenylmethylidene)hydrazino]pyridine-2-carboxylate,378 mg (3.78 mmol) of 2,4-pentanedione, 186 mg (1.08 mmol) ofparatoluenesulphonic acid and 5 mL of ethanol in a screw-top bottle.Heat the mixture at 120° C. while stirring for 48 h, then cool, andconcentrate under reduced pressure. Then distribute the residue in 50 mLof EtOAc and 50 mL of a saturated aqueous solution of NaHCO₃. Dry theorganic phase over Na₂SO₄ and concentrate under reduced pressure. Purifythe residue obtained by silica gel column chromatography, eluting with aheptane/EtOAc gradient from 0 to 50% of EtOAc. After concentration underreduced pressure, we obtain 235 mg of ethyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylatein the form of oil.

Yield=47%

18.3.6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylicacid hydrochloride

According to the debenzylation/O-alkylation/saponification stepsdescribed in examples 4.6, 1.6 and 1.7 respectively, starting from 1 g(2.25 mmol) of ethyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylate,we obtain 460 mg of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylicacid hydrochloride.

Yield=43%

18.4.1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride

According to the method described in example 9, peptide couplingeffected between 460 mg (1 mmol) of6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylicacid hydrochloride and 156 mg (1.09 mmol) of2-aminocyclohexane-2-carboxylic acid leads to 270 mg of1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride in the form of white powder.

Yield=46%

M.p. (° C.)=202

M C₂₃H₃₆ClN₃O₄=553; M+H=554

¹H NMR (ppm, d6-DMSO, 400 MHz): 12.45 (s, 1H); 10.3 (s, 1H); 8.40 (s,1H); 8.15 (s, 2H); 7.45 (d, 1H); 7.00 (m, 2H); 6.05 (s, 1H); 3.95 (t,2H); 3.15 (m, 2H); 2.75 (d, 6H); 2.20 (s, 3H); 2.15 (m, 4H); 1.70 (s,3H); 2.9-1.2 (m, 8H).

EXAMPLE NO. 191-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride Compound No. 80 19.1. 5-aminopyrazine-2-carbonitrile

Heat a suspension of 1.85 g (20.7 mmol) of copper cyanide and 1 g (20.7mmol) of sodium cyanide in 20 ml of DMF to 135° C., while stirring. Add3.6 g (20.7 mmol) of 5-bromopyrazin-2-amine to the solution obtained,and maintain the temperature of 135° C. for 18 h. Then add 2 equivalentsof sodium cyanide and of copper cyanide and continue heating for afurther 24 h. After cooling, add 100 mL of 0.3N aqueous solution ofsodium cyanide, stir the mixture for 1 h at 40° C., then distribute itin 300 mL of EtOAc/water 1:1 mixture. After washing with 2×100 mL ofwater, dry the organic phase over Na₂SO₄ and concentrate under reducedpressure. Purify the residue obtained by silica gel columnchromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 100%of EtOAc. After concentration under reduced pressure, we obtain 1.24 gof 5-aminopyrazine-2-carbonitrile in the form of oil.

Yield=50%

19.2. Methyl 5-aminopyrazine-2-carboxylate

Reflux a solution of 2.24 g (18.65 mmol) of5-aminopyrazine-2-carbonitrile and 9.45 mL (74.40 mmol) of borontrifluoride etherate in 50 mL of methanol for 2 h. Concentrate thereaction mixture under reduced pressure and take up the residue obtainedin 200 mL of EtOAc and 10 mL of a saturated aqueous solution of NaHCO₃.Dry the organic phase over Na₂SO₄ and concentrate under reducedpressure. Purify the residue obtained by silica gel columnchromatography, eluting with a cyclohexane/EtOAc 1:1 mixture. Afterconcentration under reduced pressure, we obtain 1.4 g of methyl5-aminopyrazine-2-carboxylate in the form of oil.

Yield=49%

19.3. Methyl 5-amino-6-bromopyrazine-2-carboxylate

Add 1.79 g (10.05 mmol) of N-bromosuccinimide to a solution of 1.4 g(9.14 mmol) of methyl 5-aminopyrazine-2-carboxylate in 10 mL ofacetonitrile. Stir the reaction mixture for 2 h at 20° C. thendistribute in 100 mL of EtOAc/water 1:1 mixture. Wash the organic phasewith 2×50 mL of water, dry over Na₂SO₄ and concentrate under reducedpressure. Purify the residue obtained by silica gel columnchromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 50%of EtOAc. After concentration under reduced pressure, we obtain 1.66 gof methyl 5-amino-6-bromopyrazine-2-carboxylate in the form of yellowwax.

Yield=78%

19.4. Methyl5-amino-6-[3-(benzyloxy)-4-chlorophenyl]pyrazine-2-carboxylate

Stir a suspension of 137 mg (0.36 mmol) of (bis-benzonitrile)-palladiumII dichloride and 183 mg (0.43 mmol) of diphenylphosphinobutane in 7 mLof toluene under argon for 30 min at room temperature. Then add, whilebubbling with argon, 1.66 g (7.15 mmol) of methyl5-amino-6-bromopyrazine-2-carboxylate, 1.97 g (7.51 mmol) of[3-(benzyloxy)-4-chlorophenyl]boronic acid, 2.4 mL of ethanol and 3.58mL (7.15 mmol) of a 2N aqueous solution of sodium carbonate. Reflux thereaction mixture for 5 h 30 min and then distribute in 100 mL of awater/EtOAc 1:1 mixture. Wash the organic phase with 50 mL of water, dryover Na₂SO₄ and concentrate under reduced pressure. Purify the residueobtained by silica gel column chromatography, eluting with acyclohexane/EtOAc gradient from 50 to 100% of EtOAc. After concentrationunder reduced pressure, we obtain 1.33 g of methyl5-amino-6-[3-(benzyloxy)-4-chlorophenyl]pyrazine-2-carboxylate in theform of yellow wax.

Yield=50%

19.5. Methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-bromopyrazine-2-carboxylate

Add, dropwise, 0.82 mL (6.9 mmol) of tert-butyl nitrite to a solution of1.28 g (3.46 mmol) of methyl5-amino-6-[3-(benzyloxy)-4-chlorophenyl]pyrazine-2-carboxylate in 10 mLof anhydrous acetonitrile cooled to 0° C., under argon. After 2 h at 0°C., add 1.54 g of copper dibromide and stir the suspension obtained for1 h 30 min at 65° C. After cooling, distribute the reaction mixture in100 mL of EtOAc/water 1:1 mixture. Wash the organic phase with 3×50 mLof water and 50 mL of brine, then dry over Na₂SO₄ and concentrate underreduced pressure. Purify the residue obtained by silica gel columnchromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 30%of EtOAc. After concentration under reduced pressure, we obtain 645 mgof methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-bromopyrazine-2-carboxylatein the form of yellow wax.

Yield=43%

19.6. Methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate

According to the method described in example 4.5, Suzuki couplingeffected between 545 mg (1.26 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-bromopyrazine-2-carboxylate and 205mg (1.51 mmol) of 2-methylphenylboronic acid leads to 430 mg of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylatein the form of wax.

Yield=76%

19.7.1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride

According to the debenzylation/O-alkylation/saponification/peptidecoupling steps described in examples 4.6, 1.6, 1.7 and 9, starting from485 mg (1.09 mmol) of methyl6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate,we obtain 154 mg of1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride in the form of white powder.

Yield=20%

M.p. (° C.)=162

M C₃₀H₃₅ClN₄O₄=550; M+H=551

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.40 (s, 1H); 9.15 (s, 1H); 8.40 (s,1H); 7.40 (d, 1H); 7.30 (m, 5H); 7.10 (dd, 1H); 3.85 (t, 2H); 3.15 (m,2H); 2.75 (d, 6H); 1.95 (s, 3H); 2.3-1.3 (m, 12H).

EXAMPLE NO. 201-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride Compound No. 129 20.1. Methyl3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate

Put 5 g (22.5 mmol) of methyl3-amino-5,6-dichloropyrazine-2-carboxylate, 3.2 g (23.65 mmol) of2-methylphenyl boronic acid in 45 mL of anhydrous toluene in a screw-topbottle. After dissolution, add 34 mL (67.6 mmol) of a 2N aqueoussolution of sodium carbonate and degas the two-phase mixture for 30 minby bubbling with argon. Then add 1.3 g (1.13 mmol) of Pd(PPh₃)₄ and stirthe reaction mixture vigorously at 110° C. for 48 h. After cooling,distribute the solution in 500 mL of EtOAc/brine 1:1 mixture and extractthe aqueous phase again with 4×50 mL of EtOAc. Combine the organicphases, dry over Na₂SO₄ and concentrate under reduced pressure. Purifythe residue obtained by silica gel column chromatography, eluting with acyclohexane/EtOAc gradient from 0 to 20% of EtOAc. After concentrationunder reduced pressure, we obtain 2 g of methyl3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate in the form ofyellow wax.

Yield 50%

20.2. Methyl3-amino-6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate

According to the method described previously (example 20.1), Suzukicoupling effected between 1.7 g (6.12 mmol) of methyl3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate and 3.2 g(12.24 mmol) of methyl 5-amino-6-bromopyrazine-2-carboxylate, 1.97 g(7.51 mmol) of [3-(benzyloxy)-4-chlorophenyl]boronic acid leads to 2.7 gof methyl3-amino-6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylatein the form of gum.

Yield=80%

20.3.1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride

According to the debenzylation/O-alkylation/saponification/peptidecoupling steps described in examples 4.6, 1.6, 1.7 and 9, starting from263 mg (0.57 mmol) of methyl3-amino-6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate,we obtain 40 mg of1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride in the form of white powder.

Yield=12.5%

M.p. (° C.)=138

M C₃₀H₃₆ClN₅O₄=565; M+H=566

¹H NMR (ppm, d6-DMSO, 400 MHz): 12.40 (s, 1H); 10.1 (s, 1H); 8.30 (s,1H); 7.55 (s, 2H); 7.30 (q, 1H); 7.20 (m, 4H); 7.05 (s, 1H); 6.85 (d,1H); 3.80 (t, 2H); 3.10 (m, 2H); 2.70 (s, 6H); 2.15 (d, 2H); 2.05 (m,2H); 1.95 (s, 3H); 1.75 (t, 2H); 1.55 (m, 3H); 1.40 (m, 2H); 1.25 (m,1H).

EXAMPLE NO. 211-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride Compound No. 105 21.1. 4-chloro-3-iodophenol

According to the steps of reduction/Sandmeyer reaction described inexamples 12.4 and 12.1 respectively, starting from 25 g (144 mmol) of4-chloro-3-nitrophenol we obtain 24 g of 4-chloro-3-iodophenol in theform of oil.

Yield=66%

21.2. 1-chloro-2-iodo-4-ethoxybenzene

Add 2 g (14.5 mmol) of K₂CO₃ and 1.16 mL (14.5 mmol) of iodoethane to asolution of 2.45 g (9.6 mmol) of 4-chloro-3-iodophenol in 30 mL of DMF.Heat the reaction mixture at 50° C. while stirring for 3 h, thendistribute in 200 mL of ether/water 1:1 mixture. Wash the organic phasewith 3×50 mL of water then dry over Na₂SO₄ and concentrate under reducedpressure. We obtain 2.38 g of 1-chloro-2-iodo-4-ethoxybenzene in theform of oil.

Yield=87%

21.3. (2-Chloro-5-ethoxyphenyl)boronic acid

Add, dropwise, 5.5 mL (8.8 mmol) of a 1.6N solution of butyllithium inhexane in the space of 30 min to a solution of 2.38 g (8.4 mmol) of1-chloro-2-iodo-4-ethoxybenzene in 50 mL of anhydrous THF cooled underargon to −78° C. After 2 h at −70° C., add 1.74 g (9.2 mmol) oftriisopropyl borate and stir the reaction mixture for 3 h at roomtemperature, then distribute in 200 mL of EtOAc/HCl aq 5N 1:1 mixture.Wash the organic phase with 50 mL of water, dry over Na₂SO₄ andconcentrate under reduced pressure. Purify the residue obtained bysilica gel column chromatography, eluting with a DCM/methanol gradientfrom 0 to 10% of methanol. After concentration under reduced pressure,we obtain 990 mg of (2-chloro-5-ethoxyphenyl)boronic acid, in the formof oil.

Yield=59%

21.4. Methyl5-(2-chloro-5-ethoxyphenyl)-6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}pyridine-2-carboxylate

According to the method described in example 4.5, the Suzuki reactioneffected between 452 mg (2.26 mmol) of (2-chloro-5-ethoxyphenyl)boronicacid and 1 g (1.88 mmol) of methyl6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate(obtained in 3 stages from1-chloro-4-iodo-2-[(4-methoxybenzyl)oxy]benzene according to theborylation/Suzuki coupling/triflate steps described in examples 4.2, 4.3and 4.4 respectively) leads to 700 mg of methyl5-(2-chloro-5-ethoxyphenyl)-6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}pyridine-2-carboxylatein the form of oil.

Yield=70%

21.5. Methyl5-(2-chloro-5-ethoxyphenyl)-6-(4-chloro-3-hydroxyphenyl)pyridine-2-carboxylate

Add 1 mL (13 mmol) of trifluoroacetic acid to a solution of 700 mg (1.3mmol) of methyl5-(2-chloro-5-ethoxyphenyl)-6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}pyridine-2-carboxylatein 10 mL of DCM stirred at 0° C. Stir the reaction mixture for 2 h at20° C. then concentrate under reduced pressure. Take up the residue in50 mL of DCM and wash with 50 mL of a saturated aqueous solution ofNaHCO₃. Dry the organic phase over Na₂SO₄ and concentrate under reducedpressure. Purify the residue obtained by silica gel columnchromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 30%of EtOAc. After concentration under reduced pressure, we obtain 524 mgof methyl5-(2-chloro-5-ethoxyphenyl)-6-(4-chloro-3-hydroxyphenyl)pyridine-2-carboxylatein the form of oil.

Yield=96%

21.6.1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride

According to the O-alkylation/saponification/peptide coupling stepsdescribed in examples 1.6, 1.7 and 9, starting from 524 mg (1.25 mmol)of methyl6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate,we obtain 125 mg of1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride in the form of white powder.

Yield=18%

M.p. (° C.)=160

M C₃₂H₃₇Cl₂N₃O₅=613; M+H=614

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.45 (s, 1H); 8.10 (d, 1H); 8.00 (d,1H); 7.40 (d, 2H); 7.35 (s, 1H); 7.00 (m, 3H); 4.05 (m, 2H); 3.95 (m,2H); 3.20 (m, 2H); 2.80 (s, 6H); 2.20 (d, 2H); 2.15 (m, 2H); 1.85 (t,2H); 1.65 (m, 3H); 1.45 (m, 2H); 1.35 (m, 1H); 1.30 (t, 3H).

The chemical structures and physical properties of some examples ofcompounds according to the invention are shown in the following table.

Table of Compounds

TABLE I Some of the compounds presented below are in the form ofhydrochloride. Melt- ing point No. A Z B p R₁ R₂ W X Y U (° C.)  1

(CH₂)₃ NMe₂ 0

Cl N CH H   175  2

(CH₂)₃ NMe₂ 0

Cl N CH H >200  3

(CH₂)₃ NMe₂ 0

Cl N CH H >200  4

(CH₂)₃ NMe₂ 0

Cl N CH H >200  5

(CH₂)₃ NMe₂ 0

H Cl N CH H   164  7

(CH₂)₃ NMe₂ 1 CH(Me)₂ H Cl N CH H   202  8

(CH₂)₃ NMe₂ 1

H Cl N CH H   166  9

(CH₂)₃ NMe₂ 1

H Cl N CH H   170  10

(CH₂)₃ NMe₂ 0

H Cl N CH H >200  11

(CH₂)₃ NMe₂ 1

H Cl N CH H >200  12

(CH₂)₃ NMe₂ 0

Cl N CH H >200  13

(CH₂)₃ NMe₂ 0

CH₃ Cl N CH H >200  14

(CH₂)₃ NMe₂ 0 CH(Me)₂ CH₃ Cl N CH H >200  15

(CH₂)₀

0

Cl N CH H   215  16

(CH₂)₀

0

Cl N CH H   231  17

(CH₂)₃ NMe₂ 0

Cl N CH H   184  18

(CH₂)₃ NMe₂ 0

Cl N CH H   224  19

(CH₂)₀

0

Cl N CH H   217  20

(CH₂)₂ NMe₂ 0

Cl N CH H   219  21

(CH₂)₃ NMe₂ 0

Cl N CH H   192  22

(CH₂)₃ NMe₂ 0

Cl N CH H   214  23

(CH₂)₃ NMe₂ 0

Cl N CH H   199  24

(CH₂)₃ NEt₂ 0

Cl N CH H   189  25

(CH₂)₃ NMe₂ 0

Cl N CH H   197  26

(CH₂)₃ NMe₂ 0

Cl N CH H   219  27

(CH₂)₃ NMe₂ 0

Cl N CH H   209  28

(CH₂)₃ NMe₂ 1 CH(Me)₂ H Cl CH CH H   152  29

(CH₂)₃ NMe₂ 1 CH(Me)₂ H Cl CH N H   139  30

(CH₂)₃ NMe₂ 0

H Cl N CH H   160  31

(CH₂)₂

0

Cl N CH H   175  32

(CH₂)₂

0

Cl N CH H   160  33

(CH₂)₃ NMe₂ 1

Cl N CH H 168-   170  34

(CH₂)₃ NMe₂ 0

Cl N CH H 146-   150  35

(CH₂)₃ NMe₂ 0

Cl N CH H >200  36

(CH₂)₃ NMe₂ 0

Cl N CH H   188  37

(CH₂)₃ NMe₂ 1 CH(Me)₂ enantiomer (S) H Cl H CH H   145  38

(CH₂)₃ NMe₂ 1 CH(Me)₂ enantiomer (S) H Cl H CH H   162  39

(CH₂)₃ NMe₂ 0

Cl N CH H 195-   198  40

(CH₂)₃ NMe₂ 0

Cl N CH H 178-   184  41

(CH₂)₃ NMe₂ 0

Cl N CH H   222  42

(CH₂)₃ NMe₂ 0

Cl N CH H 220-   222  43

(CH₂)₃ NMe₂ 0

CF₃ N CH H 230-   232  44

(CH₂)₃

0

Cl N CH H 208-   210  45

(CH₂)₃

0

Cl N CH H >200  46

(CH₂)₃

0

Cl N CH H >200  47

(CH₂)₂

0

Cl N CH H   185  48

(CH₂)₂

0

Cl N CH H   156  49

(CH₂)₂CHMe NMe₂ 0

Cl N CH H   196  50

CH(Me)(CH₂)₂ NMe₂ 0

Cl N CH H   188  51

(CH₂)₃ NMe₂ 0

Cl N CH H   216  52

(CH₂)₃ NMe₂ 0

Cl N CH H 188-   189  53

CH₂CH(OH)CH₂ enantiomer (S) NMe₂ 0

Cl N CH H   200  54

(CH₂)₂ NEt₂ 0

Cl N CH H   178  55

(CH₂)₃ NMe₂ 0

Cl N CH H   140  56

(CH₂)₃ NMe₂ 0

Cl N CH H >200  57

(CH₂)₃ NMe₂ 0

Cl N CH H 190-   200  58

(CH₂)₃ NMe₂ 0

Cl N CH H   174  59

(CH₂)₃ NMe₂ 0 CH(Me)₂ enantiomer (R) H Cl N CH H   138  60

(CH₂)₃ NMe₂ 0

Cl N CH H   196  61

(CH₂)₃ NMe₂ 0

Cl N CH H   172  62

(CH₂)₃ NMe₂ 1 CH(Me)₂ enantiomer (R) H Cl N CH H   145  63

CH₂CH(OH)CH₂ enantiomer (R) NMe₂ 0

Cl N CH H   200  64

(CH₂)₃ NMe₂ 0

Cl N CH H   174  65

(CH₂)₃ NMe₂ 0

Cl N CH H   165  66

(CH₂)₃ NMe₂ 0

Cl N CH H   158  67

(CH₂)₃ NMe₂ 0

Cl N CH H   150  68

(CH₂)₃ NMe₂ 0

Cl N CH H   237  69

(CH₂)₃ NMeEt 0

Cl N CH H   156  70

(CH₂)₃ NMe₂ 0

Cl N CH H   144  71

(CH₂)₃ NMe₂ 0

Cl N CH H   196  72

(CH₂)₃ NMe₂ 1 CH(Me)₂ enantiomer (S) H Cl N CH H   157  73

(CH₂)₃ NMe₂ 0

Cl N CH H   172  74

(CH₂)₃ NMe₂ 0

Cl N CH H   230  75

(CH₂)₃ NMe₂ 0

Cl N CH H   202  76

(CH₂)₃ NMe₂ 0

Cl N CH H   160  77

(CH₂)₃ NMe₂ 0

CH₂CH₃ N CH H   200  78

(CH₂)₃ NMe₂ 0

Cl N CH H   158  79

(CH₂)₃ NMe₂ 0

Cl N CH H   164  80

(CH₂)₃ NMe₂ 0

Cl N N H   162  81

(CH₂)₃ NMe₂ 1

H Cl N CH H   136  82

(CH₂)₃ NMe₂ 1

H Cl N CH H   140  83

(CH₂)₃ NMe₂ 0

Cl N CH H   175  84

(CH₂)₃ NMe₂ 0

Cl N CH H   169  85

(CH₂)₃ NMe₂ 0

Cl N CH H   146  86

(CH₂)₃ NMe₂ 0

Cl N CH H   163  87

(CH₂)₃ NMe₂ 0

Cl N CH H   117  88

(CH₂)₃ NMe₂ 0

Cl N CH H   148  89

(CH₂)₃ NMe₂ 0

Cl N CH H   186  90

(CH₂)₃ NMe₂ 0

Cl N CH H   152  91

(CH₂)₃ NMe₂ 1 C(Me)₃ H Cl N CH H   165  92

(CH₂)₃ NMe₂ 1 C(Me)₃ enantiomer (S) H Cl N CH H   170  93

(CH₂)₃ NMe₂ 0

Cl N CH H   134  94

(CH₂)₃ NMe₂ 0

Cl N CH H   144  95

(CH₂)₃ NMe₂ 0

Cl N CH H   168  96

(CH₂)₃ NMe₂ 0

Cl N CH H   147  97

(CH₂)₃ NMe₂ 0

Cl N CH H   154  98

(CH₂)₃ NMe₂ 0

Cl N CH H   149  99

(CH₂)₃ NMe(CH₂)₂OH 0

Cl N CH H   140 100

(CH₂)₃ NMe₂ 0

Cl N CH H   196 101

(CH₂)₃ NMe₂ 0

Cl N CH H   157 102

(CH₂)₃ NMe₂ 0

Cl N CH H   195 103

(CH₂)₃ NMe₂ 0

Cl N CH H   147 104

(CH₂)₃ NMe₂ 0

Cl N CH H   152 105

(CH₂)₃ NMe₂ 0

Cl N CH H   160 106

(CH₂)₃ NMe₂ 0

Cl N CH H   287 107

(CH₂)₃ NMe₂ 0

Cl N CH H   138 108

(CH₂)₃ NMe₂ 0

Cl N CH H   152 109

(CH₂)₃ NMe₂ 0

Cl N CH H   147 110

(CH₂)₃ NMe₂ 0

Cl N CH H   176 111

(CH₂)₃ NMe₂ 0

Cl N CH H   185 112

(CH₂)₃ NMe₂ 0

Cl N CH H   158 113

(CH₂)₃ NMe₂ 0

Cl N CH H   172 114

(CH₂)₃ NMe₂ 0

Cl N CH H   157 115

(CH₂)₃ NMe₂ 0

Cl N CH H   142 116

(CH₂)₃ NMe₂ 0

Cl N CHOMe H   205 117

(CH₂)₃ NMe₂ 1 C(Me)₃ enantiomer (S) H Cl N CH H   130 118

(CH₂)₃ NMe₂ 0

Cl N CH H   173 119

(CH₂)₃ NMe₂ 0

Cl N CH H   162 120

(CH₂)₃ NMe₂ 0

Cl N CH H   152 121

(CH₂)₃ NMe₂ 0

Cl N CH H   144 122

(CH₂)₃ NMe₂ 0

Cl N CH H   134 123

(CH₂)₃ NMe₂ 0

Cl N N H   135 124

(CH₂)₃ NMe₂ 0

Cl N CH H   140 125

(CH₂)₃ NMe₂ 0

Cl N CH H   148 126

(CH₂)₃ NMe₂ 0

Cl N N H   122 127

(CH₂)₃ NMe₂ 1 C(Me)₃ enantiomer (S) H Cl N N H   141 128

(CH₂)₃ NMe₂ 0

Cl N CH H   115 129

(CH₂)₃ NMe₂ 0

Cl N N NH₂   138 130

(CH₂)₃ NMe₂ 0

Cl N N NH₂   158 131

(CH₂)₃ NMe₂ 0

Cl N CH H   144 132

(CH₂)₃ NMe₂ 0

Cl N CH H   160 133

CH₂(CHF)CH₂ NMe₂ 0

Cl N CH H   158 134

(CH₂)₃ NMe₂ 0

Cl N CH H   155 135

(CH₂)₃ NMe₂ 0

Cl N CH H   274 136

(CH₂)₃ NMe₂ 0

Cl N CH NHMe   155

Table of Compounds

R₈ represents

TABLE II No. A Z B R₈ Melting point (° C.) 137

(CH₂)₃ NMe₂

170 138

(CH₂)₃ NMe₂

166 139

(CH₂)₃ NMe₂

180-190 140

(CH₂)₃ NMe₂

190-200 141

(CH₂)₃ NMe₂

160 142

(CH₂)₃ NMe₂

>250  143

(CH₂)₃ NMe₂

>250  144

(CH₂)₂

150 145

(CH₂)₃ NMeEt

160 146

(CH₂)₄ NMe₂

148 147

(CH₂)₃ NEt₂

158 148

(CH₂)₃ NMe₂

162 149

(CH₂)₃ NMe₂

170 150

(CH₂)₃ NMe₂

167-170 151

(CH₂)₃ NMe₂

202 152

(CH₂)₃ NMeEt

178 153

(CH₂)₃ NEt₂

162 154

(CH₂)₃ NMe₂

174 155

(CH₂)₃ NMe₂

170-175 156

(CH₂)₃ NMePr

138 157

(CH₂)₃ NMeEt

145 158

(CH₂)₃ NMe₂

150 159

(CH₂)₃ NMe₂

165 160

CH₂CH(Me)CH₂ NMe₂

158

The compounds according to the invention have undergone pharmacologicaltesting for determining the properties of the compounds of theinvention, including in particular:

-   -   a test in vitro of intracellular calcium mobilization (FlipR        test) employing urotensin II antagonists (the compounds of the        present invention) of the human GPR14 receptor,    -   a function test of contraction of rat aorta rings, also        employing urotensin II antagonists represented by the compounds        of the present invention.

These two tests are described below:

1. FlipR (Fluorometric Imaging Plate Reader) protocol

1.1 Purpose

The purpose is to measure the activation of the GPR14 receptor by humanurotensin II.

1.2. Test Principle

GPR14 is a Gq-coupled receptor with 7 transmembrane domains. Itsactivation by a specific ligand causes an increase in Ca²⁺ in the cellvia the PLC (Phospholipase C), IP3 (Inositol-1,4,5-triphosphate) DAG(Diacylglycerol) pathway. The increase in Ca²⁺ in the cell is measuredby means of the Fluo4AM permeating probe (mono-excitation, mono-emissionprobe) which binds to free Ca²⁺ and emits at 520 nm. The free probe isnon-fluorescent in the absence of Ca²⁺.

1.3. Protocol

Experimental Plan

1) Seeding of the cells on D−1 (Day−1) or D−2

2) Incorporation/loading (D0) of the probe (1 h)

3) Addition of the products to the FlipR and measurement

4) Addition of the ligand to the FlipR and measurement in the presenceof the products

5) Processing and exporting the data

CHOGPR14 Cells

The cells are cultivated in complete medium in Flask T225. For theexperiments, the cells are transplanted in 200 μl of culture medium in96-well (black, transparent-bottom) plates at a rate of 60 000cells/well for use on D+1 or 40 000 cells/well for use on D+2.

Incorporation of the Fluo 4 M

The Fluo-4AM is prepared at 20 mM then aliquots are taken (50 μl) andstored at −20° C. away from the light. A solution of pluronic acid at200 mg/ml in DMSO is also prepared (it has a shelf life of one week atroom temperature away from the light).

The cells are charged with the Fluo-4AM+pluronic acid mixture (aliquot50 μA+50 μA of pluronic acid) diluted to 1/100 in the measurementbuffer.

After washing the wells with 150 μA of measurement buffer (cf. annex),the cells are then charged as follows:

-   -   distribution of 100 μA of measurement buffer in each well    -   addition of 10 μA of the Fluo-4AM+pluronic acid mixture diluted        to 1/100.

The cells are incubated for 1 h at 37° C. away from the light, in anincubator in the presence of 5% CO₂.

The cells are then washed 3 times with 150 μA of measurement buffer toremove the excess of the probe. A volume of 150 μA of buffer is added toeach well at the end of washing.

After incubating the plates for 20 min at room temperature away from thelight, they are placed in the FlipR for measurement of fluorescence.

The level of basic incorporation of the Fluo-4 is checked for each plate(sd<10%) before the first injection.

After stabilization of the basic signal, the GPR14 inhibiting compoundsare injected by the FlipR under a volume of 50 μA from a dilution plateeffected with Biomek 2000 in measurement buffer. Urotensin II (3 nMfinal, concentration equal to the EC₅₀) is added under a volume of 50 μlby the FlipR on the cells from a stock plate at 15 nM diluted in themeasurement buffer. Data recording is carried out continuouslythroughout the experiment.

1.4. Data Analysis

For each plate, the basic fluorescence before injection of the compoundsis standardized by the “spatial uniformity correction” function of theFlipR. The values of fluorescence measured just before injection ofurotensin II (min) and those of the fluorescence measured at the peak ofthe effect of urotensin II (max) are exported under Excel. In eachplate, a series of wells is treated with urotensin alone in the absenceof inhibitor compound. The min and max fluorescence values for thesewells are averaged for defining 100% effect of urotensin II. Thepercentage inhibition calculated for each concentration of inhibitor iscalculated as follows:

-   -   for each well with Uro II (urotensin II)+inhibitor, calculation        of the delta product value=max−min    -   for the well with Uro II alone, calculation of the value delta        Uro II (average max−average min)

The percentage inhibition for each concentration of product iscalculated as follows:

Inhibition (%)=100×(delta Uro II−delta product)/delta Uro II

1.5. Annex

Composition of the Measurement Buffer (in Demineralized Water, to bePrepared when Required)

Qsf 500 mL QSF 1 L QSF 2 L HBSS 50 mL 100 mL 200 mL MgSO₄ 19.72 g/L 5 mL10 mL 20 mL Hepes 2.38 g 4.76 g 9.52 g Na₂CO₃ 35 g/L 5 mL 10 mL 20 mLCaCl₂ 14.7 g/L 5 mL 10 mL 20 mL BSA 10% 50 mL 100 mL 200 mL HBSS =Hanks' Balanced Salt Solution BSA = Bovine Serum Albumin

The various saline solutions can be stored for 2 months at 4° C.

Adjust the volume of H₂O and add probenecid dissolved in 1N sodiumhydroxide

+Probenecid 0.355 g in 5 mL 0.71 g in 10 mL of 1.42 g in 20 mL of 1NNaOH 1N NaOH of 1N NaOH

Check for pH 7.4.

1.6. Equipment and Materials

Human urotensin II (Bachem H-4768)

Fluo-4AM (Molecular Probes (F14202 5×1 mg)

Probenecid (Sigma P8761 100 g)

Pluronic acid (Molecular Probes P6867)

HBSS 10× (Gibco 14185-045)

HEPES (acid) (Sigma H3375)

Sodium carbonate (Sigma S7795) Na₂CO₃

Magnesium sulphate (Sigma M7774) MgSO₄

Calcium chloride (Sigma C5080) CaCl₂

Black tips (Molecular Devices 9000-0549)

Black plates, 96-well (Beckton Dickinson 356640)

DMSO (Sigma D 5879)

1.7. Results

The compounds tested have an IC50 in the FlipR test below 10000 nM. Someof these compounds have an IC50 in the FlipR test below 100 nM. Forexample, compounds No. 18, 34, 37, 58, 61, 65, 66, 67, 70, 71, 75, 79,120, 123, 129 in the table have IC50 of 19, 25, 72, 28, 9, 32, 4.2, 13,32, 24, 21, 31, 16, 4.2 and 15 nM, respectively.

2. Contraction of Rat Aorta

2.1. Protocol

Male Sprague-Dawley rats (400-500 g; C. River, France) are anaesthetizedwith 6% sodium pentobarbital (Ceva SantéAnimale) by intraperitonealinjection (0.4-0.5 ml), and then euthanized by exsanguination. Theaortas are removed, washed and, after removing the endothelium, are cutinto 4 rings of about 0.2-0.3 cm. Each fragment is placed in a containerfor isolated organs, containing 20 mL of Krebs solution with thefollowing composition (mM): NaCl 118; KCl 4.7; MgCl₂ 1.2; CaCl₂ 2.6;NaHCO₃ 25; glucose 11.1; (pH=7.4).

The tissue, maintained at 37° and aerated with a stream of carbogen (95%O₂-5% CO₂), is connected to a Grass FT03 isometric sensor under a basicstrain of 2 g, and to a Gould series 6600 amplifier for recording thevariations in strain. Data acquisition is effected automatically on anHP Compaq PC using IOX software (version 2.2) from the company Emka.

After stabilization for 60 min, the viability of the preparation istested by prestimulation with 60 mM of KCl. This contraction is repeateda second time and the strain that developed will serve as reference(100%) for standardizing the response to urotensin II.

The curve of concentration v. contractile response to urotensin II isthen constructed cumulatively until a maximum response is obtained.

A single concentration-response curve is recorded owing to thedesensitization effects induced by urotensin II.

The antagonists or the vehicle (DMSO 0.15% maximum) are added to thecontainer 30 min before the agonist.

2.2. Compound

Human urotensin II is obtained from Bachem Ltd (UK) and is dissolved in0.1% of BSA.

2.3. Data Analysis

The responses are expressed as percentage of the maximum contractionobserved with KCl. The results represent the mean+/−sem of theindividual responses. N corresponds to the number of animals per batch.

Analysis of the sigmoid curves using the Everstat software (De Lean A,Munson P J, Rodbard D., Am J Physiol 1978; 235(2): E97-102.) permittedthe EC₅₀ (concentration producing 50% of the maximum response) and theE_(max) (maximum effect) to be determined.

To evaluate the potency of the antagonists based on a singleconcentration, the pKb were calculated according to the equation:pKb=−log [antagonist]M+log(concentration-ratio−1) (Furchgott R F,Blaschko H, Muscholl E, editors. Handbook of Exp Pharmacol,Catecholamines, Springer, Berlin Heidelberg N.Y.; 1972; 33:283-335)where concentration-ratio is the EC₅₀ of the agonist in the presence ofthe antagonist divided by the EC₅₀ of the agonist in the absence of theantagonist.

If several concentrations of antagonist are tested, the pA₂ (±confidencelimits) is calculated by the Schild plot method (Arunlakshana O andSchild H O, Br J Pharmacol, 1959; 14:48-58).

2.4. Results

The compounds tested have a pKb between 5.5 and 8.15. As examples,compounds No. 18, 34, 37, 58, 61, 65, 66, 67, 70, 71, 75, 79, 120, 123,129 in the table have a pKb of 6.5; 7.1; 7.5; 6.6; 7.1; 6.5; 6.7; 6.7;6.2; 6.3; 6.6; 6.8; 7.1; 6.5; 6.8 respectively.

The compounds according to the invention can therefore be used for thepreparation of medicinal products, in particular of medicinal productsthat are inhibitors of the urotensin II receptors.

Thus, according to another of its aspects, the invention relates tomedicinal products that comprise a compound of formula (I), or a salt ofaddition of the latter to a pharmaceutically acceptable acid of thecompound of formula (I).

These medicinal products find application in therapeutics, notably inthe treatment and/or prevention of congestive heart failure, ischaemicheart disease, myocardial infarction, cardiac hypertrophy and fibrosis,coronary diseases and atherosclerosis, systemic arterial hypertension,pulmonary hypertension, portal hypertension, post-angioplastyrestenosis, renal failure and more particularly acute and chronic renalfailure of diabetic and/or hypertensive origin, diabetes, inflammationin general, fibrosis in general and aneurysms.

These medicinal products also find application in therapeutics, in thetreatment and/or prevention of disorders of the central nervous system,including notably neurodegenerative diseases, cerebrovascular accidents,stress, anxiety, aggressiveness, depression, schizophrenia, or sleepdisorders.

Medicinal products comprising compounds that are antagonists ofurotensin II such as the compounds according to the invention also findapplication in therapeutics, in the treatment and/or prevention ofvomiting.

These medicinal products also find application in therapeutics in thetreatment of some cancers. These medicinal products also findapplication in therapeutics, in the treatment and/or prevention ofasthma and respiratory diseases.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention. These pharmaceutical compositions contain aneffective dose of at least one compound according to the invention, or apharmaceutically acceptable salt of said compound, as well as at leastone pharmaceutically acceptable excipient.

Said excipients are selected according to the pharmaceutical form andthe desired method of administration, from the usual excipients that areknown by a person skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or its salt, can be administeredin unit dosage form, mixed with conventional pharmaceutical excipients,to animals and to humans for the prophylaxis or treatment of theaforementioned disorders or diseases.

The appropriate unit dosage forms comprise the forms for administrationby the oral route, such as tablets, soft or hard capsules, powders,granules and oral solutions or suspensions, forms for sublingual,buccal, intratracheal, intraocular, intranasal administration,administration by inhalation, forms for topical, transdermal,subcutaneous, intramuscular or intravenous administration, forms forrectal administration, and implants. For topical application, compoundsaccording to the invention can be used in creams, gels, ointments orlotions.

As an example, a unit dosage form of a compound according to theinvention in the form of a tablet can comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscarmellose sodium  6.0 mg Maize starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate  3.0 mg

According to another of its aspects, the present invention also relatesto a method of treatment of the above-mentioned pathologies thatcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or one of its pharmaceuticallyacceptable salts.

As used herein, the following definitions apply:

“Patient” means a warm blooded animal, such as for example rat, mice,dogs, cats, guinea pigs, and primates such as humans.

“Treat” or “treating” means to alleviate symptoms, eliminate thecausation of the symptoms either on a temporary or permanent basis, orto prevent or slow the appearance of symptoms of the named disorder orcondition.

“Therapeutically effective amount” means a quantity of the compoundwhich is effective in treating the named disorder or condition.

“Pharmaceutically acceptable carrier” is a non-toxic solvent,dispersant, excipient, adjuvant or other material which is mixed withthe active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

The citation of any reference herein should not be construed as anadmission that such reference is available as “Prior Art” to the instantapplication.

The present invention is not to be limited in scope by the specificembodiments describe herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

Various publications are cited herein, the disclosures of which areincorporated by reference in their entireties.

1. A method of treating a disease or condition selected from the groupconsisting of congestive heart failure, ischaemic heart disease,myocardial infarction, cardiac hypertrophy and fibrosis, coronarydiseases and atherosclerosis, systemic and pulmonary arterialhypertension, post-angioplasty restenosis, acute and chronic renalfailure of diabetic and/or hypertensive origin, diabetes, inflammation,fibroses and aneurysms, disorders of the central nervous system,including neurodegenerative diseases, cerebrovascular accidents, stress,anxiety, aggressiveness, depression, schizophrenia or sleep disordersand cancers or respiratory diseases, or asthma, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of formula (I):

in which: X and Y represent, independently of one another, a nitrogenatom or a —CR3- group, where R3 represents a hydrogen or halogen atom oran alkyl or alkoxy group; U represents a hydrogen atom or a group NHR7,where R7 is a hydrogen atom or an alkyl group; A represents an aryl,heteroaryl or heterocycloalkyl group optionally substituted; Wrepresents a halogen atom, an alkyl group or a haloalkyl group; Zrepresents a bond, a cycloalkylene group or an alkylene group optionallysubstituted with one or more groups selected from a halogen atom and thealkyl, hydroxy and alkoxy groups; B represents: either a group —NR4R5,where R4 and R5 represent, independently of one another, an alkyl,cycloalkyl, hydroxyalkyl or fluoroalkyl group, or alternatively R4 andR5 form, with the nitrogen atom to which they are attached, a 5- or6-membered ring, such as a pyrrolidinyl or piperidinyl ring, optionallysubstituted with an alkyl group, or a heterocycle of the followingformula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group; R1 and R2 represent: either,independently of one another, a hydrogen atom or an alkyl, cycloalkyl,phenyl, benzyl or —CH₂-indolyl group, these groups being optionallysubstituted with one or more groups selected from halogen atoms and thealkyl, fluoroalkyl, alkoxy, hydroxy and —O—CO-alkyl groups, at least oneof R1 or R2 being different from a hydrogen atom, or R1 and R2 togetherform, with the carbon atom to which they are attached, a mono- orpolycyclic system selected from: cycloalkyl, indanyl, tetrahydropyranyl,piperidine, tetrahydronaphthyl, bicyclo[2.2.1]heptyl,bicyclo[3.3.1]nonyl and adamantyl, said mono- or polycyclic system beingoptionally substituted, in any position (including on a nitrogen atom,if applicable) with one or more groups selected from a halogen atom andthe alkyl, fluoroalkyl, hydroxy, alkoxy, —O—CO-alkyl and acyl groups; prepresents an integer equal to 0 or 1; or an enantiomer, diastereomer,racemate, or pharmaceutically acceptable salt thereof.
 2. The method ofclaim 1, in which X and Y represent, independently of one another, anitrogen atom or a —CR3- group, where R3 represents a hydrogen orhalogen atom or an alkyl or alkoxy group; or an enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof. 3.The method of claim 1, in which U represents a hydrogen atom or a groupNHR7, where R7 is a hydrogen atom or an alkyl group; or an enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof. 4.The method of claim 1, in which A represents an aryl, heteroaryl orheterocycloalkyl group selected from the phenyl, benzodioxolyl, thienyl,thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl andpyrrolidinone groups, said aryl, heteroaryl or heterocycloalkyl groupbeing optionally substituted in any positions with one or more groupsselected from a halogen atom and the cyano, alkyl, haloalkyl, hydroxy,alkoxy, —O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl, —SO— and—SO₂-alkyl groups, where R and R′ represent, independently of oneanother, a hydrogen atom or an alkyl group and p is an integer between 1and 5; or an enantiomer, diastereomer, racemate, or pharmaceuticallyacceptable salt thereof.
 5. The method of claim 1, in which W representsa halogen atom, an alkyl group or a haloalkyl group; or an enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof. 6.The method of claim 1, in which Z represents a bond, a cycloalkylenegroup or an alkylene group optionally substituted with one or moregroups selected from a halogen atom and the alkyl, hydroxy and alkoxygroups; or an enantiomer, diastereomer, racemate, or pharmaceuticallyacceptable salt thereof.
 7. The method of claim 1, in which B representsa group —NR4R5, where R4 and R5 represent, independently of one another,an alkyl, cycloalkyl, hydroxyalkyl or fluoroalkyl group, oralternatively R4 and R5 form, with the nitrogen atom to which they areattached, a 5- or 6-membered ring, such as a pyrrolidinyl or piperidinylring, optionally substituted with an alkyl group, or an enantiomer,diastereomer, racemate, hydrate, solvate or pharmaceutically acceptablesalt thereof.
 8. The method of claim 1, in which B represents aheterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group; or an enantiomer, diastereomer,racemate, hydrate, solvate or pharmaceutically acceptable salt thereof.9. The method of claim 1, in which R1 and R2 represent, independently ofone another, a hydrogen atom or an alkyl, cycloalkyl, phenyl, benzyl or—CH₂-indolyl group, these groups being optionally substituted with oneor more groups selected from halogen atoms and the alkyl, fluoroalkyl,alkoxy, hydroxy and —O—CO-alkyl groups, at least one of R1 or R2 beingdifferent from a hydrogen atom, or an enantiomer, diastereomer,racemate, or pharmaceutically acceptable salt thereof.
 10. The method ofclaim 1, in which R1 and R2 together form, with the carbon atom to whichthey are attached, a mono- or polycyclic system selected from:cycloalkyl, indanyl, tetrahydropyranyl, piperidine, tetrahydronaphthyl,bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- orpolycyclic system being optionally substituted, in any position(including on a nitrogen atom, if applicable) with one or more groupsselected from a halogen atom and the alkyl, fluoroalkyl, hydroxy,alkoxy, —O—CO-alkyl and acyl groups; or an enantiomer, diastereomer,racemate, or pharmaceutically acceptable salt thereof.
 11. The method ofclaim 1, in which: X and Y represent, independently of one another, anitrogen atom or a —CR3- group, where R3 represents a hydrogen atom oran alkoxy group; U represents a hydrogen atom or a group NHR7, where R7is a hydrogen atom or an alkyl group; A represents an aryl, heteroarylor heterocycloalkyl group selected from the phenyl, benzodioxolyl,thienyl, thiazolyl, pyridinyl, pyrazolyl and pyrrolidinone groups, saidaryl or heteroaryl group being optionally substituted in any positionswith one or more groups selected from a halogen atom and the cyano,alkyl, haloalkyl, hydroxy, alkoxy, —O—(CH₂)_(p)—O-alkyl, haloalkoxy,—NRR′, —NR—CO-alkyl and —SO₂-alkyl groups, where R and R′ represent,independently of one another, a hydrogen atom or an alkyl group and p isan integer between 1 and 5; W represents a halogen atom, an alkyl groupor a haloalkyl group; Z represents a bond or an alkylene groupoptionally substituted with at least one group selected from a halogenatom and the alkyl and hydroxy groups; B represents: either a group—NR4R5, where R4 and R5 represent, independently of one another, analkyl, hydroxyalkyl group, or alternatively R4 and R5 form, with thenitrogen atom to which they are attached, a 5- or 6-membered ring, suchas a pyrrolidinyl or piperidinyl ring, or a heterocycle of the followingformula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group; R1 and R2 represent: either,independently of one another, a hydrogen atom or an alkyl, cycloalkyl,phenyl, benzyl or —CH₂-indolyl group, these groups being optionallysubstituted with one or more hydroxy groups, at least one of R1 or R2being different from a hydrogen atom, or R1 and R2 together form, withthe carbon atom to which they are attached, a mono- or polycyclic systemselected from: cycloalkyl, indanyl, tetrahydropyranyl, piperidine,bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- orpolycyclic system being optionally substituted, in any position(including on a nitrogen atom, if applicable) with one or more groupsselected from the alkyl, hydroxy and alkoxy groups; p represents aninteger equal to 0 or 1; or an enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.
 12. The method of claim 1, inwhich: X and Y represent, independently of one another, a nitrogen atomor a CH group; A represents a phenyl, pyridinyl, or pyrrolidinone group,substituted in any positions with 1 to 2 groups selected from a halogenatom, and the alkyl, trifluoromethyl, methoxy and N,N-dimethylaminegroups; U represents a hydrogen atom or a group NHR7, where R7 is ahydrogen atom; W represents a chlorine atom or a trifluoromethyl group;Z represents a bond or an alkylene group optionally substituted with amethyl group; B represents: either a group —NR4R5, where R4 and R5represent, independently of one another, an alkyl group or alternativelyR4 and R5 form, with the nitrogen atom to which they are attached, a 5-or 6-membered ring, or heterocycles of the following formula:

where m=1 or 2 and R6 represents an ethyl or methyl group; R1 and R2represent: either, independently of one another, a hydrogen atom or anisopropyl, tertbutyl group, or R1 and R2 together form, with the carbonatom to which they are attached, a mono- or polycyclic system selectedfrom: cycloalkyl, tetrahydropyranyl, bicyclo[2.2.1]heptyl,bicyclo[3.3.1]nonyl and adamantyl, said cycloalkyl group beingoptionally substituted in positions 3 and 4 with a methyl, hydroxy ormethoxy group or one or two halogen atoms, p represents 0 or 1; or anenantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof.
 13. The method of claim 1, in which: X represents a nitrogenatom and Y represents a CH group; A represents a phenyl or pyridinylgroup, substituted in positions 2, 4, 5 and 6 by one or two groupsselected from a halogen atom, such as chlorine or fluorine, and thealkyl groups, such as methyl, ethyl or isopropyl, trifluoromethyl,methoxy and N,N-dimethylamine; U represents a hydrogen atom or a groupNHR7, where R7 is a hydrogen atom; W represents a chlorine atom or atrifluoromethyl group; Z represents a bond or an ethylene, propylene ormethylpropylene group; B represents: either a group —NR4R5, where R4 andR5 represent, independently of one another, a methyl, ethyl or propylgroup or form together with the nitrogen atom to which they are attacheda 5- or 6-membered ring, or a heterocycle of the following formula:

R1 and R2 represent: either R1 is a hydrogen atom and R2 an isopropyl,tertbutyl group, the carbon atom bearing groups R1 and R2 adopting theabsolute configuration S, or R1 and R2 together form, with the carbonatom to which they are attached, a cycloalkyl, and adamantyl group, saidcycloalkyl group being optionally substituted in positions 3 and 4 witha methyl, hydroxy or methoxy group. p represents 0 or 1; or anenantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof.
 14. The method of claim 1 wherein the compound is:2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-4-methoxy-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;(3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-difluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-ethoxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dichlorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-fluoro-6-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methyl-5-(1-methylethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-chloro-5-(2-methoxyethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;(3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyrazin-2-yl]carbonyl}amino)-4,4-dimethylpentanoicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(methoxymethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-chloro-5-(1-methylethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-{[(5-[2-chloro-5-(dimethylamino)phenyl]-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethyl-6-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methyl-5-propylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)-4-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-ethoxy-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)-2-fluoropropoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)-5-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(2-methoxyethoxy)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(methoxymethyl)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methyl-5-(1-methylethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methyl-5-(2-methylpropoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(cyclopropylmethoxy)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methyl-5-propoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-2,3-dihydro-1H-indene-2-carboxylicacid;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclopentanecarboxylicacid;2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[2.2.1]heptane-2-carboxylicacid hydrochloride;N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}phenylalanine;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoicacid;3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-4-phenylbutanoicacid;3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-4-(1H-indol-3-yl)butanoicacid;({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)(phenyl)aceticacid;3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-3-cyclohexylpropanoicacid;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid;N-{([6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}-alpha-methylphenylalanine;N-{([6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}-3-methylisovaline;2-({[6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[(1-ethylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-phenylpyridin-2-yl)carbonyl]amino}adamantane-2-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;9-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-{[(2-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3.4′-bipyridin-6-yl)carbonyl]amino}adamantane-2-carboxylicacid hydrochloride;2-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylicacid hydrochloride;3-[({4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoicacid;3-({[5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride;N-{([6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}-3-hydroxyphenylalaninehydrochloride;2-({[6-{4-chloro-3-[2-(1-methylpyrrolidin-2-yl)ethoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[2-(1-methylpiperidin-2-yl)ethoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-({[6-{3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(trifluoromethyl)phenyl]pyridin-2-yl)carbonyl]amino}adamantane-2-carboxylicacid hydrochloride;2-({[6-(4-chloro-3-{3-[cyclopropyl(methyl)amino]propoxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(dimethylamino)phenyl]pyridin-2-yl)carbonyl]amino}adamantane-2-carboxylicacid hydrochloride;1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;4-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)tetrahydro-2H-pyran-4-carboxylicacid hydrochloride;(3R)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride2-[({6-[4-chloro-3-(3-piperidin-1-ylpropoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[3-(dimethylamino)butoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-[({6-[4-chloro-3-(2-piperidin-1-ylethoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylicacid hydrochloride;(3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride;2-[({6-[4-chloro-3-(2-pyrrolidin-1-ylethoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylicacid hydrochloride;2-[({6-[4-chloro-3-(3-pyrrolidin-1-ylpropoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylicacid hydrochloride;2-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-methyl-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylcyclohexanecarboxylicacid hydrochloride;2-({[6-{4-chloro-3-[3-(dimethylamino)-1-methylpropoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-methoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;(3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;2-({[6-(4-chloro-3-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;2-({[6-(4-chloro-3-{[(2S)-3-(dimethylamino)-2-hydroxypropyl]oxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;acetyl-4-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)piperidine-4-carboxylicacid hydrochloride;2-({[6-{4-chloro-3-[2-(diethylamino)ethoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;[1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexyl]aceticacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(3-amino-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-hydroxycyclohexanecarboxylicacid hydrochloride;cis-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-methoxycyclohexanecarboxylicacid hydrochloride;trans-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-methoxycyclohexanecarboxylicacid hydrochloridetrans-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(methylsulphonyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(methylsulphonyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-methyl-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(5-[2-(acetylamino)phenyl]-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;N-{([6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}-D-valinehydrochloride;1-{[(2-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2′-methyl-3.3′-bipyridin-6-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(2-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-4′-methyl-3.3′-bipyridin-6-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-[({6-[4-chloro-3-(2-pyrrolidin-1-ylethoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[4-(dimethylamino)butoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(1-methylethyl)phenyl]pyridin-2-yl)carbonyl]amino}-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-chloro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,5-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4-fluoro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-(4-chloro-3-{3-[methyl(propyl)amino]propoxy}phenyl)-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)-2-methylpropoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-3-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-propylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-fluoro-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylicacid hydrochloride;1-({[3-chloro-2′-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-2,3′-bipyridin-6′-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,5-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cycloheptanecarboxylicacid hydrochloride;(3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{3-[3-(dimethylamino)propoxy]-4-ethylphenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-cyclobutylpropanoicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylthiophen-3-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-cyclopropylpropanoicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-hydroxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4,5-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-methyl-1,3-thiazol-4-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;4-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)oxepane-4-carboxylicacid hydrochloride;3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-cyanophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3-fluoro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-6-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-(4-chloro-3-{3-[(2-hydroxyethyl)(methyl)amino]propoxy}phenyl)-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4,5-difluoro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(6-methyl-1,3-benzodioxol-5-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-diethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[5-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-(difluoromethyl)-2,3′-bipyridin-6′-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methylphenyl]-3-[methylamino]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-ethyl-3-methyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-{[(5-[2-chloro-4-(dimethylamino)phenyl]-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;(3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoicacid hydrochloride;1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-chloro-5-(trifluoromethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride;1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dichlorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-difluorocyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-(methylamino)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride;1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-methoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylicacid hydrochloride; or1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylicacid hydrochloride.
 15. A compound of formula (IV):

in which: X and Y represent, independently of one another, a nitrogenatom or a —CR3- group, where R3 represents a hydrogen or halogen atom oran alkyl or alkoxy group; U represents a hydrogen atom or a group NHR7,where R7 is a hydrogen atom or an alkyl group; A represents an aryl,heteroaryl or heterocycloalkyl group optionally substituted; Wrepresents a halogen atom, an alkyl group or a haloalkyl group; Zrepresents a bond, a cycloalkylene group or an alkylene group optionallysubstituted with one or more groups selected from a halogen atom and thealkyl, hydroxy and alkoxy groups; B represents: either a group —NR4R5,where R4 and R5 represent, independently of one another, an alkyl,cycloalkyl, hydroxyalkyl or fluoroalkyl group, or alternatively R4 andR5 form, with the nitrogen atom to which they are attached, a 5- or6-membered ring, such as a pyrrolidinyl or piperidinyl ring, optionallysubstituted with an alkyl group, or a heterocycle of the followingformula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group; or an enantiomer, diastereomer,racemate, or pharmaceutically acceptable salt thereof.
 16. The compoundof claim 15, in which X and Y represent, independently of one another, anitrogen atom or a —CR3- group, where R3 represents a hydrogen orhalogen atom or an alkyl or alkoxy group; or an enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof. 17.The compound of claim 15, in which U represents a hydrogen atom or agroup NHR7, where R7 is a hydrogen atom or an alkyl group; or anenantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof.
 18. The compound of claim 15, in which A represents an aryl,heteroaryl or heterocycloalkyl group selected from the phenyl,benzodioxolyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, pyrazolyl and pyrrolidinone groups, said aryl, heteroaryl orheterocycloalkyl group being optionally substituted in any positionswith one or more groups selected from a halogen atom and the cyano,alkyl, haloalkyl, hydroxy, alkoxy, —O—(CH₂)_(p)—O-alkyl, haloalkoxy,—NRR′, —NR—CO-alkyl, —SO— and —SO₂-alkyl groups, where R and R′represent, independently of one another, a hydrogen atom or an alkylgroup and p is an integer between 1 and 5; or an enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof. 19.The compound of claim 15, in which W represents a halogen atom, an alkylgroup or a haloalkyl group; or an enantiomer, diastereomer, racemate, orpharmaceutically acceptable salt thereof.
 20. The compound of claim 15,in which Z represents a bond, a cycloalkylene group or an alkylene groupoptionally substituted with one or more groups selected from a halogenatom and the alkyl, hydroxy and alkoxy groups; or an enantiomer,diastereomer, racemate, or pharmaceutically acceptable salt thereof. 21.The compound of claim 15, in which B represents a group —NR4R5, where R4and R5 represent, independently of one another, an alkyl, cycloalkyl,hydroxyalkyl or fluoroalkyl group, or alternatively R4 and R5 form, withthe nitrogen atom to which they are attached, a 5- or 6-membered ring,such as a pyrrolidinyl or piperidinyl ring, optionally substituted withan alkyl group, or an enantiomer, diastereomer, racemate, hydrate,solvate or pharmaceutically acceptable salt thereof.
 22. The compound ofclaim 15, in which B represents a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group; or an enantiomer, diastereomer,racemate, hydrate, solvate or pharmaceutically acceptable salt thereof.23. The compound of claim 15, in which: X and Y represent, independentlyof one another, a nitrogen atom or a —CR3- group, where R3 represents ahydrogen atom or an alkoxy group; U represents a hydrogen atom or agroup NHR7, where R7 is a hydrogen atom or an alkyl group; A representsan aryl, heteroaryl or heterocycloalkyl group selected from the phenyl,benzodioxolyl, thienyl, thiazolyl, pyridinyl, pyrazolyl andpyrrolidinone groups, said aryl or heteroaryl group being optionallysubstituted in any positions with one or more groups selected from ahalogen atom and the cyano, alkyl, haloalkyl, hydroxy, alkoxy,—O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl and —SO₂-alkylgroups, where R and R′ represent, independently of one another, ahydrogen atom or an alkyl group and p is an integer between 1 and 5; Wrepresents a halogen atom, an alkyl group or a haloalkyl group; Zrepresents a bond or an alkylene group optionally substituted with atleast one group selected from a halogen atom and the alkyl and hydroxygroups; B represents: either a group —NR4R5, where R4 and R5 represent,independently of one another, an alkyl, hydroxyalkyl group, oralternatively R4 and R5 form, with the nitrogen atom to which they areattached, a 5- or 6-membered ring, such as a pyrrolidinyl or piperidinylring, or a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, andwhere R6 and R7 represent, independently of one another, a hydrogen atomor an alkyl or cycloalkyl group; or an enantiomer, diastereomer,racemate, or pharmaceutically acceptable salt thereof.
 24. The compoundof claim 15, in which: X and Y represent, independently of one another,a nitrogen atom or a CH group; A represents a phenyl, pyridinyl, orpyrrolidinone group, substituted in any positions with 1 to 2 groupsselected from a halogen atom, and the alkyl, trifluoromethyl, methoxyand N,N-dimethylamine groups; U represents a hydrogen atom or a groupNHR7, where R7 is a hydrogen atom; W represents a chlorine atom or atrifluoromethyl group; Z represents a bond or an alkylene groupoptionally substituted with a methyl group; B represents: either a group—NR4R5, where R4 and R5 represent, independently of one another, analkyl group or alternatively R4 and R5 form, with the nitrogen atom towhich they are attached, a 5- or 6-membered ring, or heterocycles of thefollowing formula:

where m=1 or 2 and R6 represents an ethyl or methyl group; or anenantiomer, diastereomer, racemate, or pharmaceutically acceptable saltthereof.
 25. The compound of claim 15, in which: X represents a nitrogenatom and Y represents a CH group; A represents a phenyl or pyridinylgroup, substituted in positions 2, 4, 5 and 6 by one or two groupsselected from a halogen atom, such as chlorine or fluorine, and thealkyl groups, such as methyl, ethyl or isopropyl, trifluoromethyl,methoxy and N,N-dimethylamine; U represents a hydrogen atom or a groupNHR7, where R7 is a hydrogen atom; W represents a chlorine atom or atrifluoromethyl group; Z represents a bond or an ethylene, propylene ormethylpropylene group; B represents: either a group —NR4R5, where R4 andR5 represent, independently of one another, a methyl, ethyl or propylgroup or form together with the nitrogen atom to which they are attacheda 5- or 6-membered ring, or a heterocycle of the following formula:

or an enantiomer, diastereomer, racemate, or pharmaceutically acceptablesalt thereof.
 26. A compound of claim 15 in which the compound is ahydrochloride.